Pyrazole compounds, formulations thereof, and a method for using the compounds and/or formulations

ABSTRACT

Disclosed herein are embodiments of a pyrazole compound according to formula I.Compositions comprising the compound, and a method for making the composition also are disclosed. The composition may comprise a carrier, such as a polymer and/or the composition may be a spray-dried formulation. Also disclosed is a method for using the compound and/or composition. The compound and/or composition may be useful to inhibit an IRAK protein and/or to ameliorate, treat and/or prevent an IRAK-associated disease or condition in a subject.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.17/006,150, filed on Aug. 28, 2020, which claims the benefit of theearlier filing date of U.S. provisional patent application No.62/894,547, filed Aug. 30, 2019, which is incorporated herein byreference in its entirety.

FIELD

The present disclosure concerns compounds, formulations thereof, andembodiments of a method using the compounds and/or formulations, such asfor inhibiting interleukin receptor-associated kinase (IRAK) and/ordelivering an IRAK inhibitor to a subject, and for treating diseases andconditions related to IRAK.

BACKGROUND

Interleukin-1 receptor-associated kinases (IRAKs) are importantmediators of signaling processes, such as toll-like receptors (TLR) andinterleukin-1 receptor (IL-1R) signaling processes. IRAKs have beenimplicated in modulating signaling networks that control inflammation,apoptosis, and cellular differentiation. Four IRAK genes have beenidentified in the human genome (IRAK1, IRAK2, IRAK3 and IRAK4), andstudies have revealed distinct, non-redundant biological roles. IRAK1and IRAK4 have been shown to exhibit kinase activity.

SUMMARY

Disclosed herein are compounds, and compositions comprising suchcompounds that are useful as, inter alia, kinase inhibitors, such asIRAK inhibitors and/or useful for delivering an IRAK inhibitor to asubject in need thereof. In some embodiments, the compounds are prodrugsand/or salts of IRAK inhibitor compounds. Certain disclosed embodimentsconcern compounds having a formula I:

wherein R is hydrogen, aliphatic, acyl, heterocyclyl, carboxyl ester,amide, alkyl phosphoramidate, or alkyl phosphate, such as alkyl, acyl,carboxyl ester, amide, nonaromatic heterocyclyl, alkyl phosphoramidate,or alkyl phosphate. Alternatively, R is hydrogen and the compound is asalt. In some embodiments, R is C₁₋₄alkyl phosphate, C₁₋₄alkylphosphoramidate, C₁₋₆alkyl, C₁₋₆acyl, —C(O)O—C₁₋₆aliphatic,—C(O)N(R^(b))₂, or 5- or 6-membered nonaromatic heterocyclyl. And eachR^(b) independently is H, unsubstituted C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —N(R^(g))₂, carboxyl ester, or 5- or 6-membered nonaromaticheterocyclyl, or two R^(b) together with the nitrogen to which they areattached form a C₃₋₆nonaromatic heterocyclyl moiety optionallyinterrupted with one or two —O— or —N(R^(g)), where R^(g) is H orC₁₋₄alkyl. R may be C₁₋₆alkyl optionally substituted with a 5- or6-membered nonaromatic heterocyclyl, OH, —OC(O)—R^(a), —N(R^(b))₂,—OC(O)—R^(c), carboxyl, or a combination thereof, where R^(a) is5-membered nonaromatic heterocyclyl, aryl substituted with—CH₂N(R^(b))₂, C₃₋₆cycloalkyl substituted with carboxyl, C₁₋₆alkoxy,unsubstituted C₁₋₆alkyl, or C₁₋₆alkyl substituted with one or more ofN(R^(b))₂, carboxyl, carboxyl ester, —OC₁₋₆acyl, —NHC(O)(NH₂)C₁₋₆alkyl,or —(OCH₂CH₂)₁₋₈N(R^(b))₂. And, —OC(O)—R^(c) is derived from an aminoacid where the —OC(O)— moiety of —OC(O)—R^(c) corresponds to an acidmoiety on the amino acid and R^(c) comprises —N(R^(b))₂ or anitrogen-containing nonaromatic heterocyclyl. The amino acid may be anaturally occurring amino acid, and/or may be selected from glycine,valine, alanine, leucine, isoleucine, methionine, phenylalanine,tryptophan, tyrosine, serine, threonine, asparagine, glutamine,arginine, histidine, lysine, aspartic acid, glutamic acid, cysteine, orproline.

Alternatively, R may be C₁₋₆acyl moiety optionally substituted with—C(O)O—C₁₋₄alkyl, —C(O)O—C₁₋₄alkyl-N(R^(b))₂, N(R^(b))₂,—NHC(O)C₁₋₄alkyl, or a combination thereof. In some embodiments, R is 5-or 6-membered nonaromatic heterocyclyl moiety optionally substitutedwith hydroxyl, hydroxymethyl, or a combination thereof. But in otherembodiments, R is —C(O)O—C₁₋₆alkyl optionally substituted with—OC(O)C₁₋₄alkyl or N(R^(b))₂, or R is —C(O)O—C₃₋₆cycloalkyl optionallysubstituted with C₁₋₄alkyl.

In certain embodiments, R is hydrogen and the salt is a hydrochloride,citrate, hemicitrate, hemitartrate, tartrate, benzene sulfonate,mesylate, sodium, hemisuccinate, or succinate salt. But in otherembodiments, R is not a salt and/or the compound may be a prodrug of

Also disclosed herein are embodiments of a composition comprising thecompound and a pharmaceutically acceptable carrier. The composition maybe a spray-dried composition comprising a carrier and a compoundaccording to Formula I. However, with respect to the spray-driedcomposition, R may be H, aliphatic, acyl, heterocyclyl, carboxyl ester,amide, alkyl phosphoramidate, or alkyl phosphate, such as H, alkyl,acyl, carboxyl ester, amide, nonaromatic heterocyclyl, alkylphosphoramidate, or alkyl phosphate. Typically the compound according toFormula I is not in the form of a salt when spray-dried. For example,suitable compounds for spray-dried formulations disclosed herein includecompounds of Formula I wherein R is hydrogen, aliphatic, acyl,heterocyclyl, carboxyl ester or amide.

The carrier may be a polymer, for example, a cellulose derivative, vinylpolymer, lactide polymer, sugar, or a combination thereof. In someembodiments, the cellulose derivative is hydroxypropylmethylcelluloseacetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate(HPMCP), hydroxypropyl methylcellulose (HPMC), or a combination thereof;the vinyl polymer is poly(vinylpyrrolidone) (PVP),poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), or a combinationthereof; the lactide polymer is polylactide (PLA),polylactide-co-glycolide (PLGA), or a combination thereof; or the sugaris sucrose, trehalose, or a combination thereof. In certain embodiments,the carrier is hydroxypropylmethylcellulose acetate succinate, and maybe an M grade and/or fine grade hydroxypropylmethylcellulose acetatesuccinate.

The composition may comprise an effective amount of the compoundaccording to formula I, such as from 1% to 50% w/w with respect to thecarrier, or from 10% to 35% w/w with respect to the carrier.Additionally, or alternatively, the spray-dried composition may furthercomprise a flavoring, a stabilizer, a filler, or a combination thereof.And in any embodiments, the composition is amorphous, and/or may have aglass transition temperature of from 100° C. to 120° C., such as from105° C. to 110° C. or from 107° C. to 110° C.

In certain embodiments, the composition comprises 20% the disclosedcompound(s) and 80% HPMCAS-MF.

Also disclosed herein are embodiments of a method for making aspray-dried composition. The method may comprise forming a mixture ofthe compound according to formula I, a carrier and a solvent, andspray-drying the mixture to form a spray dried formulation comprisingthe compound and the carrier.

Embodiments of a method for using the disclosed compounds and/orcompositions comprising the compounds also are disclosed. The method maycomprise administering the compound of a composition comprising thecompound to a subject, such as administering an effective amount of thecompound or the composition to a subject in need thereof. The method maybe a method for treating a disease or condition for which an IRAKinhibitor is indicated.

In some embodiments, the disease is an auto-immune disease, inflammatorydisorder, cardiovascular disease, neurodegenerative disorder, allergicdisorder, multi-organ failure, kidney disease, platelet aggregation,cancer, transplantation, sperm motility, erythrocyte deficiency, graftrejection, lung injury, respiratory disease, ischemic condition,bacterial infection, viral infection, immune regulatory disorder or acombination thereof.

The method may comprise administering a second therapeutic agent. Thesecond therapeutic agent may be an analgesic, an antibiotic, ananticoagulant, an antibody, an anti-inflammatory agent, animmunosuppressant, a guanylate cyclase-C agonist, an intestinalsecretagogue, an antiviral, anticancer, antifungal, or a combinationthereof. In some embodiments, the second therapeutic agent isadministered substantially simultaneously with the compound orcomposition. In other embodiments, the second therapeutic agent isadministered sequentially in any order with the compound or composition,and the compound or composition and the second therapeutic agent may beadministered such that an effective time period of the compound orcomposition overlaps with an effective time period of the secondtherapeutic agent.

Additionally, disclosed are embodiments of a method for inhibiting anIRAK protein, comprising contacting the IRAK protein with an effectiveamount of a disclosed compound or a composition comprising the compound.And in some embodiments, the IRAK protein is in a subject.

The foregoing and other objects, features, and advantages of theinvention will become more apparent from the following detaileddescription, which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a dynamic vapor sorption (DVS) plot of percent change in massversus target relative humidity (RH), illustrating the change in mass ofone embodiment of the disclosed spray-dried formulation at 25° C. undervarious relative humidity conditions. The plot provides two isotherms: 1is the sorption plot, illustrating the change in mass with increasingrelative humidity steps; and 2 is the desorption plot, illustrating thechange in mass with decreasing relative humidity steps.

FIG. 2 is a digital image showing a polarized light microscopy (PLM)image of one embodiment of the disclosed spray-dried formulation at 400×magnification.

FIG. 3 is a graph of intensity versus scattering angle, illustrating theX-ray powder diffraction pattern of one embodiment of the disclosedspray-dried formulation.

FIG. 4 is a graph of weight and heat flow versus temperature, providingboth the thermogravimetry (TGA) and differential scanning calorimetry(DSC) plots for one embodiment of the spray-dried formulation,illustrating the weight change and heat flow of the dispersion atdifferent temperatures.

FIG. 5 is a modulated DSC (mDSC) plot of reversing heat flow versustemperature, illustrating the heat flow for one embodiment of thespray-dried formulation and showing that the glass transitiontemperature (Tg) for that embodiment is 108.3° C.

FIG. 6 is a DVS plot of percent change in mass versus target relativehumidity, illustrating the change in mass of one embodiment of acrystalline sample of compound I-1 at 25° C. under various relativehumidity conditions. The plot provides two isotherms: 1 is the sorptionplot, illustrating the change in mass with increasing relative humiditysteps; and 2 is the desorption plot, illustrating the change in masswith decreasing relative humidity steps.

FIG. 7 is a digital image showing a PLM image of a crystalline sample ofcompound I-1 at 400× magnification.

FIG. 8 is a graph of intensity versus scattering angle, illustrating theX-ray powder diffraction pattern of a crystalline sample of compoundI-1.

FIG. 9 is a graph of weight and heat flow versus temperature, providingboth the thermogravimetry (TGA) and differential scanning calorimetry(DSC) plots for a crystalline sample of compound I-1, illustrating theweight change and heat flow of the formulation at differenttemperatures.

FIG. 10 is an mDSC plot of reversing heat flow versus temperature,illustrating the heat flow for a crystalline sample of compound I-1, andshowing that the glass transition temperature (Tg) for the crystallinesample is 106.1° C.

FIG. 11 is a graph of plasma concentration versus time in hours,illustrating the individual plasma concentrations and an average plasmaconcentration resulting from administering compound I-1 as a succinateco-crystal (compound 1-106) to each of the three subjects, with theresults normalized to a dose of 5 mg/kg of compound I-1.

FIG. 12 is a graph of plasma concentration versus time in hours,illustrating the individual plasma concentrations and an average plasmaconcentration resulting from administering compound I-1 as a phosphateco-crystal (compound I-104) to each of the three subjects, with theresults normalized to a dose of 5 mg/kg of compound I-1.

FIG. 13 is a graph of plasma concentration versus time in hours,illustrating the individual plasma concentrations and an average plasmaconcentration resulting from administering compound I-1 as a gentisateco-crystal (compound I-105) to each of the three subjects, with theresults normalized to a dose of 5 mg/kg of compound I-1.

FIG. 14 is a graph of plasma concentration versus time in hours,illustrating the individual plasma concentrations and an average plasmaconcentration resulting from administering compound I-1 as a tartrateco-crystal (compound I-11) to each of the three subjects, with theresults normalized to a dose of 5 mg/kg of compound I-1.

FIG. 15 is a graph of plasma concentration versus time, illustrating theplasma concentration of compound I-1 from each of three subjects, and anaverage plasma concentration, resulting from administering a dose of oneembodiment of the disclosed spray-dried formulation sufficient toprovide of a dose of 5 mg/kg of compound I-1.

FIG. 16 is a graph of plasma concentration versus time, illustrating theplasma concentration of a metabolite of compound I-1 from each of threesubjects, and an average plasma concentration, resulting fromadministering a dose of one embodiment of the disclosed spray-driedformulation sufficient to provide of a dose of 5 mg/kg of compound I-1.

FIG. 17 is a graph of plasma concentration versus time, illustrating theplasma concentration of compound I-1 from each of three subjects, and anaverage plasma concentration, resulting from administering 5 mg/kg ofcompound I-1 as a stock solution diluted with orange juice.

FIG. 18 is a graph of plasma concentration versus time, illustrating theplasma concentration of a metabolite of compound I-1 from each of thethree subjects, and an average plasma concentration, resulting fromadministering 5 mg/kg of compound I-1 as a stock solution diluted withorange juice.

FIG. 19 is a table of pharmacokinetic data for one embodiment of thedisclosed spray-dried formulation and an organic solution/organic juiceformulation.

FIG. 20 is a DVS isotherm plot for a potassium salt of compound I-18.

FIG. 21 is a DVS isotherm plot for a arginine salt of compound I-18.

FIG. 22 is a DVS isotherm plot for a choline salt of compound I-18.

FIG. 23 is a DVS isotherm plot for a Tris salt of compound I-18.

DETAILED DESCRIPTION I. Definitions

The following explanations of terms are provided to better describe thepresent disclosure and to guide those of ordinary skill in the art inthe practice of the present disclosure. As used herein, “comprising”means “including” and the singular forms “a” or “an” or “the” includeplural references unless the context clearly dictates otherwise. Theterm “or” refers to a single element of stated alternative elements or acombination of two or more elements, unless the context clearlyindicates otherwise.

Unless explained otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood to one of ordinaryskill in the art to which this disclosure belongs. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, suitable methods andmaterials are described below. The materials, methods, and examples areillustrative only and not intended to be limiting. Other features of thedisclosure are apparent from the following detailed description and theclaims.

Unless otherwise indicated, all numbers expressing quantities ofcomponents, molecular weights, percentages, and so forth, as used in thespecification or claims are to be understood as being modified by theterm “about.” Accordingly, unless otherwise indicated, implicitly orexplicitly, the numerical parameters set forth are approximations thatmay depend on the desired properties sought and/or limits of detectionunder standard test conditions/methods. When directly and explicitlydistinguishing embodiments from discussed prior art, the embodimentnumbers are not approximates unless the word “about” is recited.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to include hydrogen so thateach carbon conforms to a valence of four. For example, in the structureon the left-hand side of the schematic below there are nine hydrogenatoms implied. The nine hydrogen atoms are depicted in the right-handstructure.

Sometimes a particular atom in a structure is described in textualformula as having a hydrogen or hydrogen atoms, for example —CH₂CH₂—. Itwill be understood by a person of ordinary skill in the art that theaforementioned descriptive techniques are common in the chemical arts toprovide brevity and simplicity to description of organic structures.

A person of ordinary skill in the art will appreciate that thedefinitions may be combined to further describe a particular compound.For example, hydroxyaliphatic refers to an aliphatic group substitutedwith an hydroxy (—OH) group, and haloalkylaryl refers to an aryl groupsubstituted with an alkyl group, where the alkyl group too issubstituted with a halogen, and where the point of attachment to theparent structure is via the aryl moiety since aryl is the base name ofthe substituent.

As used herein, the term “substituted” refers to all subsequentmodifiers in a term, for example in the term “substitutedarylC₁₋₈alkyl,” substitution may occur on the “C₁₋₈alkyl” portion, the“aryl” portion or both portions of the arylC₁₋₈alkyl group. Also by wayof example, alkyl includes substituted cycloalkyl groups.

“Substituted,” when used to modify a specified group or moiety, meansthat at least one, and perhaps two or more, hydrogen atoms of thespecified group or moiety is independently replaced with the same ordifferent substituent groups as defined below. In a particularembodiment, a group, moiety or substituent may be substituted orunsubstituted, unless expressly defined as either “unsubstituted” or“substituted.” Accordingly, any of the groups specified herein may beunsubstituted or substituted. In particular embodiments, the substituentmay or may not be expressly defined as substituted, but is stillcontemplated to be optionally substituted. For example, an “alkyl”substituent may be unsubstituted or substituted, but an “unsubstitutedalkyl” may not be substituted.

“Substituents” or “substituent groups” for substituting for one or morehydrogen atoms on saturated carbon atoms in the specified group ormoiety are, unless otherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰,—N(R⁸⁰)₂, haloalkyl, perhaloalkyl, —CN, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰, —SO₃⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —P(O)(O⁻)₂(M⁺)₂,—P(O)(O⁻)₂M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰,—C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)N(R⁸⁰)₂, —C(NR⁷⁰)(R⁸⁰)₂,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —O CO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰,—NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰ isC₁₋₆alkyl optionally substituted with 1, 2, or 3 OH; each R⁷⁰ isindependently for each occurrence hydrogen or R⁶⁰; each R⁸⁰ isindependently for each occurrence R⁷⁰ or alternatively, two R⁸⁰ groups,taken together with the nitrogen atom to which they are bonded, form a3- to 7-membered nonaromatic heterocyclyl which optionally includes from1 to 4 of the same or different additional heteroatoms selected from O,N and S, of which N optionally has H or C₁-C₃alkyl substitution; andeach M⁺ is a counter ion with a net single positive charge. Each M⁺ isindependently for each occurrence, for example, an alkali metal ion,such as K⁺, Na⁺, Li⁺; an ammonium ion, such as ⁺NH₄ or ⁺N(R⁶⁰)₄; aprotonated amino acid ion, such as a naturally occurring amino acidcounter ion, such as a lysine ion (for example, L-lysine ion), or anarginine ion, such as an L-arginine ion; an amino sugar, such asmeglumine; or an alkaline metal earth ion, such as [Ca²⁺]_(0.5),[Mg²⁺]_(0.5), or [Ba²⁺]_(0.5) (a subscript “0.5” means, for example,that one of the counter ions for such divalent alkali earth ions can bean ionized form of a compound of the invention and the other a typicalcounter ion such as chloride, or two ionized compounds can serve ascounter ions for such divalent alkali earth ions, or a doubly ionizedcompound can serve as the counter ion for such divalent alkali earthions). As specific examples, —N(R⁸⁰)₂ includes —NH₂, —NH-alkyl,—NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl,4N-methyl-piperazin-1-yl, N-morpholinyl and the like. Any two hydrogenatoms on a single carbon can be replaced with ═O, ═NR⁷¹, ═N—OR⁷⁰, ═N₂ or═S.

Substituent groups for replacing hydrogen atoms on unsaturated carbonatoms in groups containing unsaturated carbons are, unless otherwisespecified, —R⁶⁰, halo,

-   -   —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S-M⁺, —N(R⁸⁰)₂, perhaloalkyl, —CN, —OCN,        —SCN, —NO, —NO₂,    -   —N₃, —SO₂R⁷⁰, —SO₃M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰,        —PO₃ ⁻²(M⁺)₂,    -   —PO₃ ⁻²M²⁺, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰,        —C(NR⁷⁰)R⁷⁰,    -   —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)N(R⁸⁰)₂,    -   —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰,        —NR⁷⁰C(O)R⁷⁰,    -   —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂-M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,        —NR⁷⁰C(O)N(R⁸⁰)₂,    -   —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰, R⁷⁰, R⁸⁰ and        M⁺ are as previously defined, provided that in case of        substituted alkene or alkyne, the substituents are not —O⁻M⁺,        —OR⁷⁰, —SR⁷⁰, or —S-M⁺.

Substituent groups for replacing hydrogen atoms on nitrogen atoms ingroups containing such nitrogen atoms are, unless otherwise

specified, —R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S-M⁺, —N(R⁸⁰)₂,perhaloalkyl, —CN, —NO, —NO₂, —S(O)₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OS(O)₂R⁷⁰,—OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —PO₃₂-(M⁺)₂, —PO₃₂M²+, —P(O)(OR⁷⁰)O M⁺, —P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰, —C(S)R⁷⁰,—C(NR⁷⁰)R⁷⁰, —CO₂R⁷⁰, —C(S)O R⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰,—NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)N(R⁸⁰)₂, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)N(R⁸⁰)₂, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previouslydefined.

In one embodiment, a group that is substituted has 1 substituent, 2substituents, substituents, or 4 substituents.

Additionally, in embodiments where a group or moiety is substituted witha substituted substituent, the nesting of such substituted substituentsis limited to three, thereby preventing the formation of polymers. Thus,in a group or moiety comprising a first group that is a substituent on asecond group that is itself a substituent on a third group, which isattached to the parent structure, the first (outermost) group can onlybe substituted with unsubstituted substituents. For example, in a groupcomprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substitutedwith substituents that are not themselves substituted.

“Acyl” refers to the group —C(O)R, where R is H, aliphatic,heteroaliphatic, heterocyclic or aryl. Exemplary acyl moieties include,but are not limited to, —C(O)H, —C(O)alkyl, —C(O)C₁-C₆alkyl,—C(O)C₁-C₆haloalkyl-C(O)cycloalkyl, —C(O)alkenyl, —C(O)cycloalkenyl,—C(O)aryl, —C(O)heteroaryl, or —C(O)heterocyclyl. Specific examplesinclude, —C(O)H, —C(O)Me, —C(O)Et, or —C(O)cyclopropyl.

“Aliphatic” refers to a substantially hydrocarbon-based group or moiety,including alkyl, alkenyl, alkynyl groups, cyclic versions thereof, suchas cycloalkyl, cycloalkenyl or cycloalkynyl, and further includingstraight- and branched-chain arrangements, and all stereo and positionisomers as well. Unless expressly stated otherwise, an aliphatic groupcontains from one to twenty-five carbon atoms; for example, from one tofifteen, from one to ten, from one to six, or from one to four carbonatoms, and a cyclic aliphatic contains from three to twenty-five carbonatoms; for example, from three to fifteen, from three to ten, from threeto six, or from three to four carbon atoms.

“Alkyl” refers to a saturated aliphatic hydrocarbyl group having from 1to 25 carbon atoms, typically 1 to 10 carbon atoms such as 1 to 6 carbonatoms (C₁₋₆alkyl) or 1 to 4 carbon atoms, (C₁₋₄alkyl). An alkyl moietymay be substituted or unsubstituted. This term includes, by way ofexample, linear and branched hydrocarbyl groups such as methyl (CH₃),ethyl (—CH₂CH₃), n-propyl (—CH₂CH₂CH₃), isopropyl (—CH(CH₃)₂), n-butyl(—CH₂CH₂CH₂CH₃), isobutyl (—CH₂CH₂(CH₃)₂), sec-butyl (—CH(CH₃)(CH₂CH₃),t-butyl (—C(CH₃)₃), n-pentyl (—CH₂CH₂CH₂CH₂CH₃), and neopentyl(—CH₂C(CH₃)₃).

“Alkoxy” refers to the group —O-alkyl.

“Amino” refers to the group —NH₂, —NHR, or —NRR, where each Rindependently is selected from H, aliphatic, aryl or heterocyclic, ortwo R groups together with the nitrogen attached thereto form aheterocyclic ring. Examples of such heterocyclic rings include thosewherein two R groups together with the nitrogen to which they areattached form a —(CH₂)₂₋₅-ring optionally interrupted by one or twoheteroatom groups, such as —O— or —N(R^(g)) such as in the groups

wherein R^(g) is R⁷⁰, —C(O)R⁷⁰, —C(O)OR⁶⁰ or —C(O)N(R⁸⁰)₂.

“Amide” refers to the group —N(H)acyl, or —C(O)amino.

“Araliphatic” refers to an aryl group attached to the parent via analiphatic moiety. Araliphatic includes aralkyl or arylalkyl groups suchas benzyl and phenylethyl.

“Aryl” refers to an aromatic group of, unless specified otherwise, from5 to 15 ring atoms having a single ring (e.g., phenyl) or multiple fusedrings in which at least one ring is aromatic (e.g., naphthyl). Forgroups having multiple rings, at least one of which is aromatic and oneis not, such groups are nevertheless referred to as “aryl” provided thatthe point of attachment to the remainder of the compound is through anatom of an aromatic portion of the aryl group. Aryl groups may bemonocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise stated,an aryl group may be substituted or unsubstituted.

“Carboxyl,” “carboxy” or “carboxylate” refers to —CO₂H, —C(O)O⁻ or saltsthereof.

Combination: A combination includes two or more components that areadministered such that the effective time period of at least onecomponent overlaps with the effective time period of at least one othercomponent. A combination, or a component thereof, may be a composition.In some embodiments, effective time periods of all componentsadministered overlap with each other. In an exemplary embodiment of acombination comprising three components, the effective time period ofthe first component administered may overlap with the effective timeperiods of the second and third components, but the effective timeperiods of the second and third components independently may or may notoverlap with one another. In another exemplary embodiment of acombination comprising three components, the effective time period ofthe first component administered overlaps with the effective time periodof the second component, but not that of the third component; and theeffective time period of the second component overlaps with those of thefirst and third components. A combination may be a compositioncomprising the components, a composition comprising one or morecomponents and another separate component (or components) orcomposition(s) comprising the remaining component(s), or the combinationmay be two or more individual components. In some embodiments, the twoor more components may comprise the same component administered at twoor more different times, two or more different components administeredsubstantially simultaneously or sequentially in any order, or acombination thereof.

“Carboxyl ester” or “carboxy ester” refers to the group —C(O)OR, where Ris aliphatic, heteroaliphatic, and heterocyclic, including aryl andheteroaryl.

“Cycloaliphatic” refers to a cyclic aliphatic group having a single ring(e.g., cyclohexyl), or multiple rings, such as in a fused, bridged orspirocyclic system, at least one of which is aliphatic, provided thatthe point of attachment is through an atom of an aliphatic region of thecycloaliphatic group. Cycloaliphatic includes saturated and unsaturatedsystems, including cycloalkyl, cycloalkenyl and cycloalkynyl. Exemplarycycloaliphatic groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, orcyclohexenyl.

“Heteroaliphatic” refers to an aliphatic compound or group having atleast one heteroatom and at least one carbon atom, i.e., one or morecarbon atoms from an aliphatic compound or group comprising at least twocarbon atoms, has been replaced with an atom having at least one lonepair of electrons, typically nitrogen, oxygen, phosphorus, silicon, orsulfur. Heteroaliphatic compounds or groups may be substituted orunsubstituted, branched or unbranched, chiral or achiral, and/or acyclicor cyclic, such as a heterocycloaliphatic group.

“Heterocyclyl,” and “heterocycle” refer to aromatic and non-aromaticring systems, and more specifically refer to a stable three- tofifteen-membered ring moiety comprising carbon atoms and at least one,such as from one to five heteroatoms. The heterocyclyl moiety may be amonocyclic moiety, or may comprise multiple rings, such as in a bicyclicor tricyclic ring system, provided that at least one of the ringscontains a heteroatom. Such a multiple ring moiety can include fused orbridged ring systems as well as spirocyclic systems; and the nitrogen,phosphorus, carbon, silicon or sulfur atoms in the heterocyclyl moietycan be optionally oxidized to various oxidation states. For convenience,nitrogens, particularly but not exclusively, those defined as annulararomatic nitrogens, are meant to include their corresponding N-oxideform, although not explicitly defined as such in a particular example.In addition, annular nitrogen atoms can be optionally quaternized.Heterocycle includes heteroaryl or aromatic heterocyclyl moieties, andnonaromatic heterocyclyl moieties, which are heterocyclyl rings whichare partially or fully saturated. Examples of heterocyclyl groupsinclude, but are not limited to, azetidinyl, oxetanyl, acridinyl,benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl,dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane,diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,dioxaphospholanyl, and oxadiazolyl.

“Hydroxyl” refers to the group —OH.

“Pharmaceutically acceptable excipient” refers to a substance, otherthan the active ingredient or prodrug thereof, that is included in aformulation of the active ingredient. As used herein, an excipient maybe incorporated within particles of a pharmaceutical composition, or itmay be physically mixed with particles of a pharmaceutical composition.An excipient can be used, for example, to dilute an active agent and/orto modify properties of a pharmaceutical composition. Excipients caninclude, but are not limited to, antiadherents, binders, coatings,enteric coatings, disintegrants, flavorings, sweeteners, colorants,lubricants, glidants, sorbents, preservatives, adjuvants, carriers orvehicles. Excipients may be starches and modified starches, celluloseand cellulose derivatives, saccharides and their derivatives such asdisaccharides, polysaccharides and sugar alcohols, protein, syntheticpolymers, crosslinked polymers, antioxidants, amino acids orpreservatives. Exemplary excipients include, but are not limited to,magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose,starches, hydroxypropyl cellulose, hydroxypropyl methylcellulose,xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP),polyethyleneglycol (PEG), tocopheryl polyethylene glycol 1000 succinate(also known as vitamin E TPGS, or TPGS), carboxy methyl cellulose,dipalmitoyl phosphatidyl choline (DPPC), vitamin A, vitamin E, vitaminC, retinyl palmitate, selenium, cysteine, methionine, citric acid,sodium citrate, methyl paraben, propyl paraben, sugar, silica, talc,magnesium carbonate, sodium starch glycolate, tartrazine, aspartame,benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulphiteor lanolin.

An “adjuvant” is an excipient that modifies the effect of other agents,typically the active ingredient. Adjuvants are often pharmacologicaland/or immunological agents. An adjuvant may modify the effect of anactive ingredient by increasing an immune response. An adjuvant may alsoact as a stabilizing agent for a formulation. Exemplary adjuvantsinclude, but are not limited to, aluminum hydroxide, alum, aluminumphosphate, killed bacteria, squalene, detergents, cytokines, paraffinoil, and combination adjuvants, such as freund's complete adjuvant orfreund's incomplete adjuvant.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound that are derived from a variety of organic andinorganic counter ions as will be known to a person of ordinary skill inthe art and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, tris(hydroxymethyl)aminomethane(tris) and the like; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate, benzene sulfonate,tosylate, succinate, acetate, maleate, oxalate, and the like.“Pharmaceutically acceptable acid addition salts” are a subset of“pharmaceutically acceptable salts” that retain the biologicaleffectiveness of the free bases while formed by acid partners. Inparticular, the disclosed compounds form salts with a variety ofpharmaceutically acceptable acids, including, without limitation,inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like, as well as organicacids such as formic acid, acetic acid, trifluoroacetic acid, propionicacid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonicacid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionicacid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, xinafoic acid, gentisic acid, and the like.“Pharmaceutically acceptable base addition salts” are a subset of“pharmaceutically acceptable salts” that are derived from inorganicbases such as sodium, potassium, lithium, ammonium, calcium, magnesium,iron, zinc, copper, manganese, aluminum salts and the like. Exemplarysalts are the ammonium, potassium, sodium, calcium, and magnesium salts.Salts derived from pharmaceutically acceptable organic bases include,but are not limited to, salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine(for example, L-lysine), arginine (for example, L-arginine), histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, meglumine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins, and thelike.

Exemplary organic bases are isopropylamine, diethylamine,tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine,dicyclohexylamine, choline, and caffeine. (See, for example, S. M.Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19which is incorporated herein by reference.) In particular disclosedembodiments, the compound is in the form of a benzene sulfonate,hydrochloride, sodium, succinate, tris, mesylate, or tartrate salt.

“Phosphate” refers to the group —O—P(O)(OR′)₂, where each —OR′independently is —OH, —O-aliphatic, such as —O-alkyl, —O-aryl, or—O-aralkyl, or —OR′ is —O⁻M⁺, where M⁺ is a counter ion with a singlepositive charge as disclosed herein. For example, each M⁺ may be analkali ion, such as K⁺, Na⁺, Li⁺; an ammonium ion, such as ⁺N(R″)₄ whereeach R″ independently is H, aliphatic, such as alkyl, hydroxyalkyl, or acombination thereof, heterocyclyl, or aryl; an amino acid, such asarginine or lysine; an amino sugar, such as meglumine; or an alkalineearth ion, such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5). Alkylphosphate refers to the group -alkyl-phosphate, such as,—CH₂O—P(O)(OR′)₂ or —CH₂(CH₃)O—P(O)(OR′)₂ for example,—CH₂OP(O)(O-isopropyl)₂, —CH₂OP(O)(OH)(O-tert-butyl),—CH₂OP(O)(O-tert-butyl)₂, —CH₂OP(O)(OCH₂OCO₂isopropyl)₂, —CH₂OP(O)(OH)₂,or a salt thereof, such as —CH₂OP(O)(O⁻Na⁺)₂, —CH₂OP(O)(O⁻)₂Mg²+, or—CH₂OP(O)(OH)(O⁻Na⁺)

“Phosphoramidate” refers to the group —O—P(O)(OR′)(N(R′)₂), where eachR′ independently is H, aliphatic, such as alkyl, aryl, or aralkyl, or—OR′ is —O⁻M⁺, and where M⁺ is a counter ion with a single positivecharge, as disclosed herein. For example, each M⁺ may be an alkali ion,such as K⁺, Na⁺, Li⁺; an ammonium ion, such as ⁺N(R″)₄ where each R″independently is H, aliphatic, such as alkyl, hydroxyalkyl, or acombination thereof, heterocyclyl, or aryl; an amino acid, such asarginine or lysine; an amino sugar, such as meglumine; or an alkalineearth ion, such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5). Alkylphosphoramidate refers to the group -alkyl-phosphoramidate, such as, forexample, —CH₂O—P(O)(OR′)(N(R′₂)) or —CH₂(CH₃)O—P(O)(OR′)(N(R′₂)), suchas, —CH₂OP(O)(O-phenyl)[NHC(CH₃)CO₂isopropyl], or—CH₂OP(O)(OH)(N(H)alkyl), or a salt thereof, such as—CH₂OP(O)(O⁻Na⁺)(N(H)alkyl).

“Pharmaceutically acceptable carrier” refers to an excipient that is acarrier or vehicle, such as a suspension aid, solubilizing aid, oraerosolization aid. Pharmaceutically acceptable carriers areconventional. Remington: The Science and Practice of Pharmacy, TheUniversity of the Sciences in Philadelphia, Editor, Lippincott,Williams, & Wilkins, Philadelphia, PA, 21^(st) Edition (2005), describescompositions and formulations suitable for pharmaceutical delivery ofone or more therapeutic compositions and additional pharmaceuticalagents.

In general, the nature of the carrier will depend on the particular modeof administration being employed. For instance, parenteral formulationsusually comprise injectable fluids that include pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. In some examples, the pharmaceutically acceptable carrier maybe sterile to be suitable for administration to a subject (for example,by parenteral, intramuscular, or subcutaneous injection). In addition tobiologically-neutral carriers, pharmaceutical compositions to beadministered can contain minor amounts of non-toxic auxiliarysubstances, such as wetting or emulsifying agents, preservatives, and pHbuffering agents and the like, for example sodium acetate or sorbitanmonolaurate.

“Effective amount” with respect to a compound or composition refer to anamount of the compound or composition sufficient to achieve a particulardesired result, such as to inhibit a protein or enzyme, particularly aninterleukin-1 receptor-associated kinase; to elicit a desired biologicalor medical response in a tissue, system, subject or patient; to treat aspecified disorder or disease; to ameliorate or eradicate one or more ofits symptoms; and/or to prevent the occurrence of the disease ordisorder. The amount of a compound which constitutes an “effectiveamount” may vary depending on the compound, the desired result, thedisease state and its severity, the age of the patient to be treated,and the like.

“Prodrug” refers to compounds that are transformed in vivo to yield abiologically active compound, particularly the parent compound, forexample, by hydrolysis in the gut or enzymatic conversion. Typically, aprodrug compound of a compound has less activity against a desiredbiological target that the parent compound. A prodrug negligible or lessactivity with respect to a desired target until it is metabolized to theactive form. Common examples of prodrug moieties include, but are notlimited to, ester, amide, carbamate, and urea forms of a compound havingan active form bearing a carboxylic acid moiety. Examples ofpharmaceutically acceptable esters of the compounds of this inventioninclude, but are not limited to, esters of phosphate groups andcarboxylic acids, such as aliphatic esters, particularly alkyl esters(for example C₁₋₆alkyl esters). Other prodrug moieties include phosphateesters, such as —(CH₂)_(n)—O—P(O)(OR′)₂, wherein n is 1 or 2 and R′ is Hor C₁₋₆alkyl, such as —CH₂—O—P(O)(OR′)₂ wherein each R′ is independentlyH or C₁₋₆alkyl, when at least one R′ is H, the phosphate moiety can bein the form of a salt, such as a mono or dianion salt with an organic orinorganic cationic counter ion. Acceptable esters also includecycloalkyl esters and arylalkyl esters such as, but not limited tobenzyl. Examples of pharmaceutically acceptable amides of the compoundsof this invention include, but are not limited to, primary amides, andsecondary and tertiary alkyl amides (for example with between one andsix carbons). Amides and esters of disclosed exemplary embodiments ofcompounds according to the present invention can be prepared accordingto conventional methods. A thorough discussion of prodrugs is providedin T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Spray-dried dispersion” refers to a single-phase dispersion of acompound or compounds in a polymer matrix. Typically, the compound orcompounds are amorphous.

“Subject” refers to humans and non-human subjects.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of the solute. The solvent can be an organiccompound, an inorganic compound, or a mixture of both. Some examples ofsolvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.The compounds described herein can exist in un-solvated as well assolvated forms when combined with solvents, pharmaceutically acceptableor not, such as water, ethanol, and the like. Solvated forms of thepresently disclosed compounds are within the scope of the embodimentsdisclosed herein.

The above definitions and the following general formulas are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluoro groups). Such impermissible substitutionpatterns are easily recognized by a person having ordinary skill in theart.

Any of the groups referred to herein may be optionally substituted by atleast one, possibly two or more, substituents as defined herein. Thatis, a substituted group has at least one, possible two or more,substitutable hydrogens replaced by a substituent or substituents asdefined herein, unless the context indicates otherwise or a particularstructural formula precludes substitution.

A person of ordinary skill in the art will appreciate that compounds mayexhibit the phenomena of tautomerism, conformational isomerism,geometric isomerism, and/or optical isomerism. For example, certaindisclosed compounds can include one or more chiral centers and/or doublebonds and as a consequence can exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers,diastereomers, and mixtures thereof, such as racemic mixtures. Asanother example, certain disclosed compounds can exist in severaltautomeric forms, including the enol form, the keto form, and mixturesthereof. As the various compound names, formulae and compound drawingswithin the specification and claims can represent only one of thepossible tautomeric, conformational isomeric, optical isomeric, orgeometric isomeric forms, it would be understood that the disclosedcompounds encompass any tautomeric, conformational isomeric, opticalisomeric, and/or geometric isomeric forms of the compounds describedherein, as well as mixtures of these various different isomeric forms.In cases of limited rotation, e.g. around the amide bond or between twodirectly attached rings such as the pyrazole and pyridinyl rings,atropisomers are also possible and are also specifically included in thecompounds of the invention.

Particular examples of the presently disclosed compounds include one ormore asymmetric centers; thus these compounds can exist in differentstereoisomeric forms. Accordingly, compounds and compositions may beprovided as individual pure enantiomers or diastereomers, or asstereoisomeric mixtures, including racemic mixtures. In certainembodiments the compounds disclosed herein are synthesized in or arepurified to be in substantially enantiopure form, such as in at least90% enantiomeric excess, 95% enantiomeric excess, 97% enantiomericexcess, 98% enantiomeric excess, 99% enantiomeric excess, 99.5%enantiomeric excess, or greater than 99.5% enantiomeric excess, such asin enantiopure form.

In any embodiments, any or all hydrogens present in the compound, or ina particular group or moiety within the compound, may be replaced by adeuterium or a tritium. Thus, a recitation of alkyl includes deuteratedalkyl, where from one to the maximum number of hydrogens present may bereplaced by deuterium. For example, ethyl may be C₂H₅ or C₂H₅ where from1 to 5 hydrogens are replaced by deuterium.

II. Compounds

Disclosed herein are pyrazole compounds, methods of making thecompounds, and methods of using the compounds. In one embodiment, thedisclosed compounds are tyrosine kinase inhibitors and/or may be usefulin blocking one or more cytokine signaling pathways, such as the IL-17signaling pathway. For certain embodiments, the pyrazole compounds areuseful for treating conditions in which inhibition of an interleukin-1receptor-associated kinase (IRAK) pathway is therapeutically useful. Insome embodiments, the compounds inhibit an IRAK protein, such as IRAK1,IRAK2, IRAK3 or IRAK4. In other embodiments, the compounds are usefulfor delivering an IRAK inhibitor compound, and/or may be a prodrug of anIRAK inhibitor. In certain embodiments, the pyrazole compound is aprodrug of

In some embodiments, the pyrazole compound has a general formula I

With respect to formula I, R is H, aliphatic, acyl, heterocyclyl,carboxyl ester, amide, alkyl phosphoramidate, or alkyl phosphate. Aperson of ordinary skill in the art understands that Formula I alsoincludes solvates, co-crystals, salts, and/or N-oxides of the compounds,as well as free base compounds. In some embodiments, R is not H, oralternatively, R is hydrogen. When R is hydrogen the compound may be afree base or in the form of a salt. In other embodiments, R is alkyl,acyl, carboxyl ester, amide, nonaromatic heterocyclyl, alkylphosphoramidate, or alkyl phosphate. A person of ordinary skill in theart understands that compounds where R is not H may act a prodrug of thecompound where R is H, for example, when administered to a subject.

In one aspect, the compound of Formula I is in the form of a co-crystal.Examples of co-crystals include, but are not limited to, a succinateco-crystal, a phosphate co-crystal, a gentisate co-crystal, or atartrate co-crystal.

In some embodiments, R is H, C₁₋₄alkyl phosphate, C₁₋₄alkylphosphoramidate, C₁₋₆alkyl, C₁₋₆acyl, —C(O)O—C₁₋₆aliphatic,—C(O)N(R^(b))₂, or 5- or 6-membered nonaromatic heterocyclyl, but incertain embodiments, R is not H, or R is H and the compound is a salt.

With respect to the R moiety, the C₁₋₆alkyl moiety may be unsubstituted,or it may be substituted, such as with a 5- or 6-membered nonaromaticheterocyclyl, OH, —OC(O)—R^(a), —N(R^(b))₂, —OC(O)—R^(c), carboxyl, or acombination thereof;

-   -   the C₁₋₆acyl moiety may be unsubstituted or it may be        substituted with —C(O)O—C₁₋₄alkyl, —C(O)O—C₁₋₄alkyl-N(R^(b))₂,        N(R^(b))₂, —NHC(O)C₁₋₄alkyl, or a combination thereof;    -   the 5- or 6-membered heterocyclyl moiety may be a 5- or        6-membered oxygen-containing heterocyclyl, and/or may be        substituted with hydroxyl, hydroxymethyl, or a combination        thereof; or    -   the —C(O)O—C₁₋₆aliphatic may be —C(O)O⁻C₁₋₆alkyl optionally        substituted with —OC(O)C₁₋₄alkyl, or N(R^(b))₂, or the        —C(O)O—C₁₋₆aliphatic may be —C(O)O⁻C₃₋₆cycloalkyl optionally        substituted with C₁₋₄alkyl.

In any embodiments, each R^(a) independently is 5-membered nonaromaticheterocyclyl, aryl substituted with —CH₂N(R^(b))₂, C₃₋₆cycloalkylsubstituted with carboxyl, C₁₋₆alkoxy, unsubstituted C₁₋₆alkyl, orC₁₋₆alkyl substituted with one or more, such as 1, 2 or 3, of N(R^(b))₂,carboxyl, carboxyl ester, —OC₁₋₆acyl, —NHC(O)(NH₂)C₁₋₆alkyl, or—(OCH₂CH₂)₁₋₈N(R^(b))₂;

-   -   each R^(b) independently is H, unsubstituted C₁₋₆alkyl,        C₁₋₆alkyl substituted with —N(R^(g))₂, carboxyl ester, or 5- or        6-membered nonaromatic heterocyclyl, or two R^(b) together with        the nitrogen to which they are attached form a C₃₋₆nonaromatic        heterocyclyl moiety optionally interrupted with one or two —O—        or —N(R^(g)), where R^(g) is H or C₁₋₄alkyl; and —OC(O)—R^(c) is        derived from an amino acid where the —OC(O)— moiety of        —OC(O)—R^(c) corresponds to an acid moiety on the amino acid,        and R^(c) comprises —N(R^(b))₂ or a nitrogen-containing        nonaromatic heterocyclyl, such as a 5- or 6-membered unsaturated        nitrogen-containing heterocyclyl, for example, pyrrolidinyl. The        amino acid can be any amino acid, such as a naturally occurring        amino acid, and may be an amino acid selected from glycine,        valine, alanine, leucine, isoleucine, methionine, phenylalanine,        tryptophan, tyrosine, serine, threonine, asparagine, glutamine,        arginine, histidine, lysine, aspartic acid, glutamic acid,        cysteine, or proline. A person of ordinary skill in the art will        understand that where the amino acid comprises one or more        chiral center, all enantiomers, diastereomers and/or mixtures        thereof are contemplated. For example, the amino acid may be the        L-amino acid, the D-amino acid or a mixture thereof. In some        embodiments, the amino acid is the L-amino acid. And in certain        embodiments, —OC(O)—R^(c) is —OC(O)CH(NH₂)R^(d),

or —OC(O)—(CH₂)₁₋₂C(NH₂)CO₂H, where R^(d) is an amino acid side chain,and/or may be H, —CH₃, isopropyl, —CH₂CH(CH₃)₂, —CH(CH₃)Et, —CH₂CH₂SCH₃,

—CH₂OH, —CH(OH)CH₃, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂SH,—CH₂CH₂CH₂NHC(O)(NH)NH₂,

—CH₂CH₂CH₂CH₂NH₂, —CH₂CO₂H, or CH₂CH₂CO₂H.

In any embodiments, the compound may be a salt, such as apharmaceutically acceptable salt as defined herein, and in someembodiments, the salt is a hydrochloride, citrate, hemicitrate,hemitartrate, tartrate, benzene sulfonate, mesylate, sodium,hemisuccinate, or succinate salt.

Some exemplary compounds according to formula I include:

Exemplary compounds according to formula I include:

-   I-1:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-2:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    dihydrogen phosphate;-   I-3: di-tert-butyl    ((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)    phosphate;-   I-4:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    phosphate disodium salt;-   I-5:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-6:    2-(1-(acetyl-L-leucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-7: 1-methylcyclopropyl    4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;-   I-8: 1-(isobutyryloxy)ethyl    4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;-   I-9:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-10: 2-morpholinoethyl    4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;-   I-11:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    hemi-tartrate salt;-   I-12:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(morpholine-4-carbonyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-13:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((3-morpholinopropyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-14:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((3-(dimethylamino)propyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-15: 3-morpholinopropyl    4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;-   I-16:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    L-valinate hydrochloride;-   I-17:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    L-prolinate hydrochloride;-   I-18:    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    dihydrogen phosphate;-   I-19:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    glycinate hydrochloride;-   I-20:    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    phosphate disodium salt;-   I-21:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    (S)-2-amino-3,3-dimethylbutanoate hydrochloride;-   I-22:    2-(1-acetyl-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-23:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    2-amino-2-methylpropanoate hydrochloride;-   I-24:    4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic    acid;-   I-25: methyl    4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate;-   I-26:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(2-morpholinoacetyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-27:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(2-hydroxy-3-morpholinopropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-28:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    2-morpholinoacetate;-   I-29:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    L-valinate;-   I-30:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    L-valinate benzene sulfonate;-   I-31:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    L-valinate mesylate;-   I-32: 2-(4-methylpiperazin-1-yl)ethyl    4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate;-   I-33:    1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)    4-methyl L-aspartate hydrochloride;-   I-34: methyl    N-(2-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-2-oxoethyl)-N-methylglycinate;-   I-35:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    (S)-2-amino-3,3-dimethylbutanoate;-   I-36:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    (S)-2-amino-3,3-dimethylbutanoate benzene sulfonate;-   I-37:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    4-(morpholinomethyl)benzoate;-   I-38:    4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)    1-methyl L-aspartate hydrochloride;-   I-39:    (1R,2R)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic    acid;-   I-40:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    (S)-2-amino-3,3-dimethylbutanoate mesylate;-   I-41:    (S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic    acid hydrochloride;-   I-42:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4S)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((2S,3S,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-43:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4R)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-44: tert-butyl    (1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl)    hydrogen phosphate sodium acetate salt;-   I-45:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    isopropyl carbonate;-   I-46:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    di(((isopropoxycarbonyl)oxy)methyl) phosphate;-   I-47:    1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)    4-methyl L-aspartate;-   I-48:    1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)    4-methyl L-aspartate benzene sulfonate;-   I-49:    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    dihydrogen phosphate tris salt;-   I-50:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    glycinate benzene sulfonate;-   I-51: 2-(4-methylpiperazin-1-yl)ethyl    4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate    benzene sulfonate;-   I-52: 2-(4-methylpiperazin-1-yl)ethyl    4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate    succinate salt;-   I-53:    (2R,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic    acid;-   I-54:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    acetate;-   I-55:    4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)    1-methyl L-aspartate benzene sulfonate;-   I-56:    4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic    acid tris salt;-   I-57:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    4-((S)-2-amino-3-methylbutanamido)butanoate hydrochloride;-   I-58:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-59:    2-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)acetic    acid;-   I-60:    ((((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(hydroxy)phosphoryl)oxy)methyl    isopropyl carbonate;-   I-61:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate hydrochloride;-   I-62: isopropyl    (((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;-   I-63:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    dihydrogen phosphate tris salt;-   I-64:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    hydrochloride;-   I-65:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    benzene sulfonate;-   I-66:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    tartrate;-   I-67:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    sodium salt;-   I-68:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    hemicitrate;-   I-69:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    dihydrogen phosphate ditris salt;-   I-70: benzyl    ((S)-1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate;-   I-71:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    L-prolinate;-   I-72:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    glycinate;-   I-73:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    (R)-2-amino-3,3-dimethylbutanoate;-   I-74:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    2-amino-2-methylpropanoate;-   I-75:    4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)    1-methyl L-aspartate;-   I-76:    (S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic    acid;-   I-77:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    4-((S)-2-amino-3-methylbutanamido)butanoate;-   I-78:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate;-   I-79:    2-(1-(acetyl-D-leucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-80:    2-(1-(acetylleucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;-   I-81:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    D-valinate;-   I-82:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    valinate;-   I-83:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    D-prolinate;-   I-84:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    prolinate;-   I-85:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    2-amino-3,3-dimethylbutanoate;-   I-86:    (1S,2S)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic    acid;-   I-87:    (1R,2S)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic    acid;-   I-88:    (1S,2R)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic    acid;-   I-89:    2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic    acid;-   I-90:    (R)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic    acid;-   I-91:    2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic    acid;-   I-92:    4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)    1-methyl D-aspartate;-   I-93:    4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)    1-methyl aspartate;-   I-94:    1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)    4-methyl D-aspartate;-   I-95:    1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)    4-methyl aspartate;-   I-96:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    4-((R)-2-amino-3-methylbutanamido)butanoate;-   I-97:    (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl    4-(2-amino-3-methylbutanamido)butanoate;-   I-98: isopropyl    (((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate;-   I-99: isopropyl    (((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)alaninate;-   I-100:    (2R,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic    acid;-   I-101:    (2S,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic    acid;-   I-102:    (2S,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic    acid;-   I-103:    2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic    acid;-   I-104:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    phosphate;-   I-105:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    gentisate;-   I-106:    N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide    succinate;-   I-107: sodium    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    hydrogen phosphate;-   I-108: potassium    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    hydrogen phosphate;-   I-109: potassium    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    phosphate;-   I-110:    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    dihydrogen phosphate arginine salt;-   I-111:    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    dihydrogen phosphate choline salt;-   I-112: ammonium    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    hydrogen phosphate;-   I-113:    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    dihydrogen phosphate lysine salt;-   I-114:    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    dihydrogen phosphate meglumine salt;-   I-115: magnesium    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    phosphate; or-   I-116: Calcium    1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl    phosphate.

III. Compositions and/or Combinations Comprising Pyrazole Compounds

A. Combinations with Other Therapeutic Agents

The pyrazole compounds of the present invention may be used alone, incombination with one another, or as an adjunct to, or in combinationwith, other established therapies. In another aspect, the compounds ofthe present invention may be used in combination with other therapeuticagents useful for the disorder or condition being treated. Thesecompounds may be administered simultaneously, sequentially in any order,by the same route of administration, or by a different route.

In some embodiments, the second therapeutic agent is an analgesic, anantibiotic, an anticoagulant, an antibody, an anti-inflammatory agent,an immunosuppressant, a guanylate cyclase-C agonist, an intestinalsecretagogue, an antiviral, anticancer, antifungal, a cell therapy, or acombination thereof. The anti-inflammatory agent may be a steroid or anonsteroidal anti-inflammatory agent. In certain embodiments, thenonsteroidal anti-inflammatory agent is selected from aminosalicylates,cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen,flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin,meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen,oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combinationthereof. In some embodiments, the immunosuppressant is mercaptopurine, acorticosteroid, an alkylating agent, a calcineurin inhibitor, an inosinemonophosphate dehydrogenase inhibitor, antilymphocyte globulin,antithymocyte globulin, an anti-T-cell antibody, or a combinationthereof. In one embodiment, the antibody is infliximab.

In some embodiments, the present compounds may be used with anti-canceror cytotoxic agents. Various classes of anti-cancer and anti-neoplasticcompounds include, but are not limited to, alkylating agents,antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes,antibiotics, enzymes, cytokines, platinum coordination complexes,proteasome inhibitors, substituted ureas, kinase inhibitors, hormonesand hormone antagonists, and hypomethylating agents, for example DNMTinhibitors, such as azacitidine and decitabine. Exemplary alkylatingagents include, without limitation, mechlorothamine, cyclophosphamide,ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines,alkyl sulfonates (e.g., busulfan), and carmustine. Exemplaryantimetabolites include, by way of example and not limitation, folicacid analog methotrexate; pyrimidine analog fluorouracil, cytosinearbinoside; purine analogs mercaptopurine, thioguanine, andazathioprine. Exemplary vinca alkyloids include, by way of example andnot limitation, vinblastine, vincristine, paclitaxel, and colchicine.Exemplary antibiotics include, by way of example and not limitation,actinomycin D, daunorubicin, and bleomycin. An exemplary enzymeeffective as an anti-neoplastic agent includes L-asparaginase. Exemplarycoordination compounds include, by way of example and not limitation,cisplatin and carboplatin. Exemplary hormones and hormone relatedcompounds include, by way of example and not limitation,adrenocorticosteroids prednisone and dexamethasone; aromatase inhibitorsamino glutethimide, formestane, and anastrozole; progestin compoundshydroxyprogesterone caproate, medroxyprogesterone; and anti-estrogencompound tamoxifen.

These and other useful anti-cancer compounds are described in MerckIndex, 13th Ed. (O'Neil M. J. et al., ed.) Merck Publishing Group (2001)and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12thEdition, Brunton L. L. ed., Chapters 60-63, McGraw Hill, (2011), both ofwhich are incorporated by reference herein.

Among the CTLA 4 antibodies that can be used in combination with thepresently disclosed inhibitors is ipilimumab, marketed as YERVOY® byBristol-Myers Squibb.

Other chemotherapeutic agents for combination include immunooncologyagents, such as checkpoint pathway inhibitors, for example, PD-1inhibitors, such as nivolumab and lambrolizumab, and PD-L1 inhibitors,such as pembrolizumab, MEDI-4736 and MPDL3280A/RG7446. Additionalcheckpoint inhibitors for combination with the compounds disclosedherein include, Anti-LAG-3 agents, such as BMS-986016 (MDX-1408).

Further chemotherapeutic agents for combination with the presentlydisclosed inhibitors include Anti-SLAMF7 agents, such as the humanizedmonoclonal antibody elotuzumab (BMS-901608), anti-KIR agents, such asthe anti-KIR monoclonal antibody lirilumab (BMS-986015), and anti-CD137agents, such as the fully human monoclonal antibody urelumab(BMS-663513).

Additional anti-proliferative compounds useful in combination with thecompounds of the present invention include, by way of example and notlimitation, antibodies directed against growth factor receptors (e.g.,anti-Her2); and cytokines such as interferon-α and interferon-γ,interleukin-2, and GM-CSF.

Additional chemotherapeutic agents useful in combination with thepresent pyrazole compounds include proteasome inhibitors, such asbortezomib, carfilzomib, marizomib and the like.

Examples of cell therapies include, but are not limited to, cellsexpressing chimeric antigen receptors (CARs) and/or T cell receptors(TCRs). YESCARTA and KYMRIAH are two commercially available examples.

Examples of kinase inhibitors that are useful in combination with thepresently disclosed compounds, particularly in treating malignancies,include Btk inhibitors, such as ibrutinib, CDK inhibitors, such aspalbociclib, EGFR inhibitors, such as afatinib, erlotinib, gefitinib,lapatinib, osimertinib and vandetinib, Mek inhibitors, such astrametinib, Raf inhibitors, such as dabrafenib, sorafenib andvemurafenib, VEGFR inhibitors, such as axitinib, lenvatinib, nintedanib,pazopanib, BCR-Abl inhibitors, such as bosutinib, dasatinib, imatiniband nilotinib, Syk inhibitors, such as fostamatinib, and JAK inhibitors,such as ruxolitinib, In other embodiments, the second therapeutic agentmay be selected from any of the following:

-   -   analgesics—morphine, fentanyl, hydromorphone, oxycodone,        codeine, acetaminophen, hydrocodone, buprenorphine, tramadol,        venlafaxine, flupirtine, meperidine, pentazocine,        dextromoramide, dipipanone;    -   antibiotics—aminoglycosides (e.g., amikacin, gentamicin,        kanamycin, neomycin, netilmicin, tobramycin, and paromycin),        carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin,        and meropenem), cephalosporins (e.g., cefadroxil, cefazolin,        cefalotin, cephalexin, cefaclor, cefamandole, cefoxitin,        cefprozil, cefuroxime, cefixime, cefdinir, cefditoren,        cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten,        ceftizoxime, ceftriaxone, cefepime, and cefobiprole),        glycopeptides (e.g., teicoplanin, vancomycin, and telavancin),        lincosamides (e.g., clindamycin and incomysin), lipopeptides        (e.g., daptomycin), macrolides (e.g., azithromycin,        clarithromycin, dirithromycin, erythromycin, roxithromycin,        troleandomycin, telithromycin, and spectinomycin), monobactams        (e.g., aztreonam), nitrofurans (e.g., furazolidone and        nitrofurantoin), penicillins (e.g., amoxicillin, ampicillin,        azlocillin, carbenicillin, cloxacillin, dicloxacillin,        flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin,        penicillin G, penicillin V, piperacillin, temocillin, and        ticarcillin), penicillin combinations (e.g.,        amoxicillin/clavulanate, ampicillin/sulbactam,        piperacillin/tazobactam, and ticarcillin/clavulanate),        polypeptides (e.g., bacitracin, colistin, and polymyxin B),        quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin,        levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid,        norfloxacin, ofloxacin, trovafloxacin, grepafloxacin,        sparfloxacin, and temafloxacin), sulfonamides (e.g., mafenide,        sulfonamidochrysoidine, sulfacetamide, sulfadiazine, silver        sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilimide,        sulfasalazine, sulfisoxazole, trimethoprim, and        trimethoprim-sulfamethoxaxzole), tetracyclines (e.g.,        demeclocycline, doxycycline, minocycline, oxytetracycline, and        tetracycline), antimycobacterial compounds (e.g., clofazimine,        dapsone, capreomycin, cycloserine, ethambutol, ethionamide,        isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin,        rifapentine, and streptomycin), and others, such as        arsphenamine, chloramphenicol, fosfomycin, fusidic acid,        linezolid, metronidazole, mupirocin, platensimycin,        quinuprisin/dalfopristin, rifaximin, thiamphenicol, tigecycline,        and timidazole;    -   antibodies—anti-TNF-α antibodies, e.g., infliximab (Remicade™),        adalimumab, golimumab, certolizumab; anti-B cell antibodies,        e.g., rituximab; anti-IL-6 antibodies, e.g., tocilizumab;        anti-IL-1 antibodies, e.g., anakinra; anti PD-1 and/or        anti-PD-L1 antibodies, e.g. nivolumab, pembrolizumab,        pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736;        ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab,        clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab,        sarilumab, secukinumab, toralizumab, zanolimumab;    -   anticoagulants—warfarin (Coumadin™), acenocoumarol,        phenprocoumon, atromentin, phenindione, heparin, fondaparinux,        idraparinux, rivaroxaban, apixaban, hirudin, lepirudin,        bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin,        hementin;    -   anti-inflammatory agents—steroids, e.g., budesonide,        nonsteroidal anti-inflammatory agents, e.g., aminosalicylates        (e.g., sulfasalazine, mesalamine, olsalazine, and balsalazide),        cyclooxygenase inhibitors (COX-2 inhibitors, such as rofecoxib,        celecoxib), diclofenac, etodolac, famotidine, fenoprofen,        flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin,        meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen,        oxaprozin, piroxicam, salsalate, sulindac, tolmetin;    -   immunosuppressants—mercaptopurine, corticosteroids such as        dexamethasone, hydrocortisone, prednisone, methylprednisolone        and prednisolone, alkylating agents such as cyclophosphamide,        calcineurin inhibitors such as cyclosporine, sirolimus and        tacrolimus, inhibitors of inosine monophosphate dehydrogenase        (IMPDH) such as mycophenolate, mycophenolate mofetil and        azathioprine, and agents designed to suppress cellular immunity        while leaving the recipient's humoral immunologic response        intact, including various antibodies (for example,        antilymphocyte globulin (ALG), antithymocyte globulin (ATG),        monoclonal anti-T-cell antibodies (OKT3)) and irradiation.        Azathioprine is currently available from Salix Pharmaceuticals,        Inc. under the brand name Azasan; mercaptopurine is currently        available from Gate Pharmaceuticals, Inc. under the brand name        Purinethol; prednisone and prednisolone are currently available        from Roxane Laboratories, Inc.; Methyl prednisolone is currently        available from Pfizer; sirolimus (rapamycin) is currently        available from Wyeth-Ayerst under the brand name Rapamune;        tacrolimus is currently available from Fujisawa under the brand        name Prograf; cyclosporine is current available from Novartis        under the brand name Sandimmune and Abbott under the brand name        Gengraf; IMPDH inhibitors such as mycophenolate mofetil and        mycophenolic acid are currently available from Roche under the        brand name Cellcept and Novartis under the brand name Myfortic;        azathioprine is currently available from Glaxo Smith Kline under        the brand name Imuran; and antibodies are currently available        from Ortho Biotech under the brand name Orthoclone, Novartis        under the brand name Simulect (basiliximab) and Roche under the        brand name Zenapax (daclizumab); and    -   Guanylate cyclase-C receptor agonists or intestinal        secretagogues—for example linaclotide, sold under the name        Linzess.

These various agents can be used in accordance with their standard orcommon dosages, as specified in the prescribing information accompanyingcommercially available forms of the drugs (see also, the prescribinginformation in the 2006 Edition of The Physician's Desk Reference), thedisclosures of which are incorporated herein by reference.

B. Compositions Comprising Pyrazole Compounds

The disclosed pyrazole compounds may be used alone, in any combination,and in combination with, or adjunctive to, at least one secondtherapeutic agent, and further the pyrazole compounds, and the at leastone second therapeutic if present, may be used in combination with anysuitable additive useful for forming compositions for administration toa subject. Additives can be included in pharmaceutical compositions fora variety of purposes, such as to dilute a composition for delivery to asubject, to facilitate processing of the formulation, to provideadvantageous material properties to the formulation, to facilitatedispersion from a delivery device, to stabilize the formulation (e.g.,antioxidants or buffers), to provide a pleasant or palatable taste orconsistency to the formulation, or the like. Typical additives include,by way of example and without limitation: pharmaceutically acceptableexcipients; pharmaceutically acceptable carriers; and/or adjuvants, suchas mono-, di-, and polysaccharides, sugar alcohols and other polyols,such as, lactose, glucose, raffinose, melezitose, lactitol, maltitol,trehalose, sucrose, mannitol, starch, or combinations thereof;surfactants, such as sorbitols, diphosphatidyl choline, and lecithin;bulking agents; buffers, such as phosphate and citrate buffers;anti-adherents, such as magnesium stearate; binders, such as saccharides(including disaccharides, such as sucrose and lactose), polysaccharides(such as starches, cellulose, microcrystalline cellulose, celluloseethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers(such as polyvinylpyrrolidone, polyalkylene gylcols); coatings (such ascellulose ethers, including hydroxypropylmethyl cellulose, shellac, cornprotein zein, and gelatin); release aids (such as enteric coatings);disintegrants (such as crospovidone, crosslinked sodium carboxymethylcellulose, and sodium starch glycolate); fillers (such as dibasiccalcium phosphate, vegetable fats and oils, lactose, sucrose, glucose,mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavorsand sweeteners (such as mint, cherry, anise, peach, apricot or licorice,raspberry, and vanilla; lubricants (such as minerals, exemplified bytalc or silica, fats, exemplified by vegetable stearin, magnesiumstearate or stearic acid); preservatives (such as antioxidantsexemplified by vitamin A, vitamin E, vitamin C, retinyl palmitate, andselenium, amino acids, exemplified by cysteine and methionine, citricacid and sodium citrate, parabens, exemplified by methyl paraben andpropyl paraben); colorants; compression aids; emulsifying agents;encapsulation agents; gums; granulation agents; and combinationsthereof.

IV. Method of Use

The present disclosure provides pyrazole compounds and combinationsand/or compositions thereof, that may be useful to ameliorate, treatand/or prevent a variety of diseases and/or disorders. Certain disclosedcompounds, referred to herein as active compounds, have activity as IRAKinhibitors and/or may be used to ameliorate, treat or prevent a diseaseand/or disorder when administered at a dose that provides a desiredbenefit to the subject but does not cause significant unwanted and/orharmful side effects to the subject. In some embodiments, the diseaseand/or disorder is one for which an IRAK inhibitor is indicated. Thepresent disclosure also addresses the problem of administering and/orproviding a biologically effective amount of such an active compound toa subject, such as a subject in need of an IRAK inhibitor. Certainembodiments concern pyrazole compounds that are useful to provide and/ordeliver a biologically effective amount of an active compound to thesubject. Such compounds may be a prodrug of the active compound, a saltof the active compound, or a combination thereof. Also disclosed areembodiments of a formulation comprising one or more of the pyrazolecompounds that are useful for delivering the active compound, a prodrugand/or salt of the active compound, or a combination thereof. Certainembodiments of the composition concern a spray-dried formulation.

A. Diseases/Disorders

The disclosed pyrazole compounds, as well as combinations and/orcompositions thereof, may be useful to ameliorate, treat and/or preventa variety of diseases and/or disorders. In particular embodiments, thepyrazole compound, combinations of pyrazole compounds, and/orcompositions thereof, may be useful for treating or preventingauto-immune diseases, inflammatory disorders, cardiovascular diseases,nerve disorders, neurodegenerative disorders, allergic disorders,asthma, pancreatitis, multi-organ failure, kidney diseases, plateletaggregation, cancer, transplantation, sperm motility, erythrocytedeficiency, graft rejection, lung injuries, respiratory diseases,ischemic conditions, cytokine release syndrome (CRS), and bacterial andviral infections.

In some embodiments, the pyrazole compound, combinations of pyrazolecompounds, and/or compositions thereof, may be useful or treating orpreventing allergic diseases, amyotrophic lateral sclerosis (ALS),systemic lupus erythematosus, rheumatoid arthritis, type I diabetesmellitus, inflammatory bowel disease, biliary cirrhosis, uveitis,multiple sclerosis, Crohn's disease, ulcerative colitis, bullouspemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener'sgranulomatosis, ichthyosis, Graves ophthalmopathy or asthma.

The pyrazole compound, combinations of pyrazole compounds, and/orcompositions thereof, may also be useful for ameliorating, treating orpreventing immune regulatory disorders related to bone marrow or organtransplant rejection or graft-versus-host disease. Examples ofinflammatory and immune regulatory disorders that can be treated withthe present compounds include, but are not limited to, transplantationof organs or tissue, graft-versus-host diseases brought about bytransplantation, autoimmune syndromes including rheumatoid arthritis,systemic lupus erythematosus, Hashimoto's thyroiditis, multiplesclerosis, systemic sclerosis, myasthenia gravis, type I diabetes,uveitis, posterior uveitis, allergic encephalomyelitis,glomerulonephritis, postinfectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis, inflammatory andhyperproliferative skin diseases, psoriasis, atopic dermatitis, contactdermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichenplanus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupuserythematosus, acne, alopecia areata, keratoconjunctivitis, vernalconjunctivitis, uveitis associated with Behcet's disease, keratitis,herpetic keratitis, conical cornea, dystrophia epithelialis corneae,corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves'opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollenallergies, reversible obstructive airway disease, bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, bronchitis, gastric ulcers, vascular damage causedby ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns, celiac diseases, proctitis,eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerativecolitis, migraine, rhinitis, eczema, interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy,multiple myositis, Guillain-Barre syndrome, Meniere's disease,polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjögren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenesis, metastasis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis, sclerosing cholangitis, partial liver resection,acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock,or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis,alcoholic liver disease, including alcoholic cirrhosis, non-alcoholicsteatohepatitis (NASH), hepatic failure, fulminant hepatic failure,late-onset hepatic failure, “acute-on-chronic” liver failure,augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMVinfection, AIDS, cancer, senile dementia, Parkinson's disease, trauma,or chronic bacterial infection.

In certain embodiments, the present compounds are useful for treatingnerve pain, including neuropathic pain and inflammation induced pain.

In certain embodiments, the pyrazole compound, combinations of pyrazolecompounds, and/or compositions thereof, are useful for treating and/orpreventing rheumatoid arthritis, psoriatic arthritis, osteoarthritis,systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis,osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, inparticular pustular psoriasis, type I diabetes, type II diabetes,inflammatory bowel disease (Crohn's disease and ulcerative colitis),hyperimmunoglobulinemia d and periodic fever syndrome,cryopyrin-associated periodic syndromes, Schnitzler's syndrome, systemicjuvenile idiopathic arthritis, adult's onset Still's disease, gout, goutflares, pseudogout, sapho syndrome, Castleman's disease, sepsis, stroke,atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptorantagonist), Alzheimer's disease, or Parkinson's disease.

Proliferative diseases that may be treated by the pyrazole compound,combinations of pyrazole compounds, and/or compositions thereof, includebenign or malignant tumors, solid tumor, carcinoma of the brain, kidney,liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries,colon, rectum, prostate, pancreas, lung, vagina, cervix, testis,genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma,glioblastomas, neuroblastomas, multiple myeloma, gastrointestinalcancer, especially colon carcinoma or colorectal adenoma, a tumor of theneck and head, an epidermal hyperproliferation, psoriasis, prostatehyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma,adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cellcarcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkins andNon-Hodgkins, a mammary carcinoma, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,IL-1 driven disorders, a MyD88 driven disorder (such as ABC diffuselarge B-cell lymphoma (DLBCL), Waldenström's macroglobulinemia,Hodgkin's lymphoma, primary cutaneous T-cell lymphoma or chroniclymphocytic leukemia), smoldering or indolent multiple myeloma, orhematological malignancies (including leukemia, acute myeloid leukemia(AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chroniclymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS),myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenström'smacroglobulinemia (WM), splenic marginal zone lymphoma, multiplemyeloma, plasmacytoma, or intravascular large B-cell lymphoma). Inparticular, the presently disclosed compounds are useful for treatingdrug resistant malignancies, such as those resistant to JAK inhibitors,ibrutinib resistant malignancies, including ibrutinib resistanthematological malignancies, such as ibrutinib resistant CLL andibrutinib resistant Waldenström's macroglobulinemia.

Examples of allergic disorders that may be treated using the pyrazolecompound, combinations of pyrazole compounds, and/or compositionsthereof, include, but are not limited to, asthma (e.g. atopic asthma,allergic asthma, atopic bronchial IgE-mediated asthma, non-atopicasthma, bronchial asthma, non-allergic asthma, essential asthma, trueasthma, intrinsic asthma caused by pathophysiologic disturbances,essential asthma of unknown or unapparent cause, emphysematous asthma,exercise-induced asthma, emotion-induced asthma, extrinsic asthma causedby environmental factors, cold air induced asthma, occupational asthma,infective asthma caused by or associated with bacterial, fungal,protozoal, or viral infection, incipient asthma, wheezy infant syndrome,bronchiolitis, cough variant asthma or drug-induced asthma), allergicbronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennialallergic rhinitis, perennial rhinitis, vasomotor rhinitis, post-nasaldrip, purulent or non-purulent sinusitis, acute or chronic sinusitis,and ethmoid, frontal, maxillary, or sphenoid sinusitis.

As another example, rheumatoid arthritis (RA) typically results inswelling, pain, loss of motion and tenderness of target jointsthroughout the body. RA is characterized by chronically inflamedsynovium that is densely crowded with lymphocytes. The synovialmembrane, which is typically one cell layer thick, becomes intenselycellular and assumes a form similar to lymphoid tissue, includingdendritic cells, T-, B- and NK cells, macrophages and clusters of plasmacells. This process, as well as a plethora of immunopathologicalmechanisms including the formation of antigen-immunoglobulin complexes,eventually result in destruction of the integrity of the joint,resulting in deformity, permanent loss of function and/or bone erosionat or near the joint. The pyrazole compound, combinations of pyrazolecompounds, or compositions thereof, may be used to treat, ameliorate orprevent any one, several or all of these symptoms of RA. Thus, in thecontext of RA, the compounds are considered to provide therapeuticbenefit when a reduction or amelioration of any of the symptoms commonlyassociated with RA is achieved, regardless of whether the treatmentresults in a concomitant treatment of the underlying RA and/or areduction in the amount of circulating rheumatoid factor (“RF”).

The American College of Rheumatology (ACR) has developed criteria fordefining improvement and clinical remission in RA. Once such parameter,the ACR20 (ACR criteria for 20% clinical improvement), requires a 20%improvement in the tender and swollen joint count, as well as a 20%improvement in 3 of the following 5 parameters: patient's globalassessment, physician's global assessment, patient's assessment of pain,degree of disability, and level of acute phase reactant. These criteriahave been expanded for 50% and 70% improvement in ACR50 and ACR70,respectively. Other criteria include Paulu's criteria and radiographicprogression (e.g. Sharp score).

In some embodiments, therapeutic benefit in patients suffering from RAis achieved when the patient exhibits an ACR20. In specific embodiments,ACR improvements of ACRC50 or even ACR70 may be achieved.

B. Formulations and Administration

Pharmaceutical compositions comprising the active compounds of theinvention (or prodrugs thereof) may be manufactured by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilization processes. Thecompositions may be formulated in conventional manner using one or morephysiologically acceptable excipients, diluents, carriers, adjuvants orauxiliaries to provide preparations which can be used pharmaceutically.

The active compound or a prodrug thereof may be formulated in thepharmaceutical compositions per se, or in the form of a hydrate,solvate, N-oxide, co-crystal, or pharmaceutically acceptable salt.Typically, such salts are more soluble in aqueous solutions than thecorresponding free acids and bases, but salts having lower solubilitythan the corresponding free acids and bases may also be formed.

Pharmaceutical compositions of the invention may take a form suitablefor virtually any mode of administration, including, for example,topical, ocular, oral, buccal, systemic, nasal, injection, such as i.v.or i.p., transdermal, rectal, vaginal, etc., or a form suitable foradministration by inhalation or insufflation.

For topical administration, the active compound(s), hydrate, solvate,N-oxide, co-crystal, or pharmaceutically acceptable salt and/orprodrug(s) may be formulated as solutions, gels, ointments, creams,suspensions, etc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions may also contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multidosecontainers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile, pyrogen-free water, buffer, dextrose solution, etc., beforeuse. To this end, the pyrazole compound(s) maybe dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients, such as:binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); and/or wetting agents (e.g., sodiumlauryl sulfate). The tablets may be coated by methods well known in theart with, for example, sugars, films or enteric coatings.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable additives such as:suspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, cremophore™ or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the pyrazolecompound(s) may be formulated as solutions (for retention enemas)suppositories or ointments containing conventional suppository bases,such as cocoa butter or other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s), hydrate, solvate, N-oxide,co-crystal, pharmaceutically acceptable salt and/or prodrug(s) can beconveniently delivered in the form of an aerosol spray from pressurizedpacks or a nebulizer with the use of a suitable propellant, e.g.)dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound or prodrug (0.5 to20 mg/ml); benzalkonium chloride (0.1 to 0.2 mg/mL); polysorbate 80(TWEEN® 80; 0.5 to 5 mg/ml); carboxymethylcellulose sodium ormicrocrystalline cellulose (1 to 15 mg/ml); phenylethanol (14 mg/ml);and dextrose (20 to 50 mg/ml). The pH of the final suspension can beadjusted to range from about pH 5 to pH 7, with a pH of about pH 5.5being typical.

Another specific example of an aqueous suspension suitable foradministration of the compounds via inhalation contains 20 mg/mLCompound or prodrug, 1% (v/v) Polysorbate 80 (TWEEN® 80), 50 mM citrateand/or 0.9% sodium chloride.

For ocular administration, the active compound(s) or prodrug(s) may beformulated as a solution, emulsion, suspension, etc. suitable foradministration to the eye. A variety of vehicles suitable foradministering compounds to the eye are known in the art. Specificnon-limiting examples are described in U.S. Pat. Nos. 6,261,547;6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222;5,403,841; 5,077,033; 4,882,150; and 4,738,851, which are incorporatedherein by reference.

For prolonged delivery, the pyrazole compound(s) can be formulated as adepot preparation for administration by implantation or intramuscularinjection. The pyrazole compound maybe formulated with suitablepolymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptionmay be used. To this end, permeation enhancers may be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. Nos. 5,407,713;5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189;5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which areincorporated herein by reference.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver the pyrazole compound(s). Certain organicsolvents, such as dimethylsulfoxide (DMSO), may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

I. Spray-Dried Formulation

Disclosed herein are embodiments of a spray-dried formulation comprisingone or more compounds according to formula I. The spray-driedformulation may be a dispersion, such as a spray-dried dispersion of thecompound(s) according to formula I in a carrier or matrix, such as apolymer matrix. Typically, the spray-dried formulation comprises asingle phase, amorphous dispersion of the disclosed compound(s) in thecarrier, such as a polymer matrix.

Embodiments of the spray-dried formulation comprise, consist essentiallyof, or consist of, an effective amount of one or more compoundsaccording to formula I and an amount of the carrier sufficient to formthe spray-dried formulation. A person of ordinary skill in the art willappreciate that an effective amount of the compound(s) may vary, buttypically the effective amount is from 0.1% to 50% (w/w with respect tothe carrier) or more, such as from 1% to 50%, from 5% to 40%, from 10%to 35%, from 15% to 30%, or from 15% to 25%. In particular embodiments,the spray-dried formulation comprises, consists essentially of, orconsists of, 20% w/w of the disclosed compound(s) and 80% w/w carrier,such as a polymer matrix.

In some embodiments, the carrier is a polymer, such as a polymer that issuitable to form a spray-dried formulation with the disclosedcompound(s). Suitable polymers include, but are not limited to,cellulose derivatives, such as hydroxypropylmethylcellulose acetatesuccinate (hypromellose acetate succinate; HPMCAS), hydroxypropylmethylcellulose phthalate (hypromellose phthalate; HPMCP) orhydroxypropyl methylcellulose (HPMC); vinyl polymers, such aspoly(vinylpyrrolidone) (PVP), or poly(vinylpyrrolidone-co-vinyl acetate)(PVPVA); lactide polymers, such as polylactide (PLA) orpolylactide-co-glycolide (PLGA); sugars, such as sucrose or trehalose;or any combination thereof. In certain embodiments, the carrier isHPMCAS. The polymer, such as HPMCAS, may be of any grade suitable toform the spray-dried formulation, such as grade L, grade M, or grade H.In particular embodiments, grade M is used. Additionally, the HPMCAS maybe a fine grade (F) or a granular grade (G), and in certain embodiments,fine grade is used. And in certain working embodiments, the carrier isHPMCAS-MF.

In some embodiments, the spray-dried formulation has a suitable glasstransition temperature. The glass transition temperature may be from100° C. or less to 120° C. or more, such as from 105° C. to 110° C. or107° C. to 110° C. In certain working embodiments, the glass transitiontemperature is from 108° C. to 109° C.

In some embodiments, the formulation may comprise additional components.Additional components can be included in pharmaceutical compositions fora variety of purposes, such as to dilute a composition for delivery to asubject, to facilitate processing of the formulation, to provideadvantageous material properties to the formulation, to facilitatedispersion from a delivery device, to stabilize the formulation (e.g.,antioxidants or buffers), to provide a pleasant or palatable taste orconsistency to the formulation, or the like. Typical additionalcomponents include, by way of example and without limitation:pharmaceutically acceptable excipients; pharmaceutically acceptablecarriers; and/or adjuvants, such as mono-, di-, and polysaccharides,sugar alcohols and other polyols, such as, lactose, glucose, raffinose,melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, orcombinations thereof; surfactants, such as sorbitols, diphosphatidylcholine, and lecithin; bulking agents; buffers, such as phosphate andcitrate buffers; anti-adherents, such as magnesium stearate; binders,such as saccharides (including disaccharides, such as sucrose andlactose), polysaccharides (such as starches, cellulose, microcrystallinecellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin,synthetic polymers (such as polyvinylpyrrolidone, polyalkylene gylcols);coatings (such as cellulose ethers, including hydroxypropylmethylcellulose, shellac, corn protein zein, and gelatin); release aids (suchas enteric coatings); disintegrants (such as crospovidone, crosslinkedsodium carboxymethyl cellulose, and sodium starch glycolate); fillers(such as dibasic calcium phosphate, vegetable fats and oils, lactose,sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesiumstearate); flavors and sweeteners (such as mint, cherry, anise, peach,apricot or licorice, raspberry, and vanilla; lubricants (such asminerals, exemplified by talc or silica, fats, exemplified by vegetablestearin, magnesium stearate or stearic acid); preservatives (such asantioxidants exemplified by vitamin A, vitamin E, vitamin C, retinylpalmitate, and selenium, amino acids, exemplified by cysteine andmethionine, citric acid and sodium citrate, parabens, exemplified bymethyl paraben and propyl paraben); colorants; compression aids;emulsifying agents; encapsulation agents; gums; granulation agents; andcombinations thereof.

II. Method of Making a Spray-Dried Formulation

Embodiments of a method for making the spray-dried formulation are alsodisclosed herein. In some embodiments, one or more compounds accordingto formula I and the polymer are dissolved in a suitable solvent ormixture of solvents, and then spray-dried. Suitable solvent(s) includeany solvent or mixture of solvents that dissolves the disclosedcompound(s) and the carrier and is suitable for a spray-drying process.Exemplary solvents include, but are not limited to, alcohol, such asmethanol, ethanol, isopropanol, n-propanol, and the like; chlorinatedsolvents, such as dichloromethane, chloroform. In some embodiments, thedisclosed compound(s) is dissolved in the solvent or mixture ofsolvents, and the polymer is added to the mixture. However, in otherembodiments, the polymer is dissolved first and the compound(s) issubsequently added, or the compound(s) and the polymer are mixedsubstantially simultaneously with the solvent or solvent mixture.Regardless of the order of addition, the mixture typically is mixeduntil the disclosed compound(s) and the polymer are dissolved, and/orthe mixture has a uniform appearance. In some embodiments, the resultingmixture is stored at a reduced temperature, such as below 25° C., orfrom less than 25° C. to 0° C., from 15° C. to 0° C., from 10° C. to 0°C., or from 7° C. to 3° C., typically at about 5° C. The solution alsomay be protected from light, i.e. stored in a dark environment.

The solution is then spray-dried using a spray drying apparatus.Suitable spray-drying apparatuses are known to persons of ordinary skillin the art. In some embodiments, the parameters of the spray dryingapparatus, such as feed temperature, inlet temperature, target outlettemperature and aspiration are set to values suitable for the disclosedcompound(s) and the polymer, as understood by a person of ordinary skillin the art. In certain embodiments, the feed temperature is from 15° C.or less to 35° C. or more, such as from 20° C. to 25° C. The inlettemperature may be from 40° C. or less to 60° C. or more, such as from45° C. to 55° C. The target outlet temperature may be from 30° C. orless to 45° C. or more, such as from 32° C. to 42° C. or from 34° C. to40° C. And/or the aspirator may be from 50% or more to 100%, such asfrom 70% to 100% or from 80% to 100%.

The resulting spray-dried solid may be further dried at a temperaturesuitable to remove at least some, and may be substantially all, of anyremaining solvent without substantially degrading the disclosedcompound(s) and/or the carrier. In some embodiments, the solid is driedat a temperature of from 25° C. to 100° C. or more, such as from 30° C.to 75° C., or from 35° C. to 50° C. The dispersion may be dried untilsubstantially all the remaining solvent has been removed, and/or untilno further weight loss is achieved. The drying may continue for from 1hour to 48 hours or more, such as from 6 hours to 36 hours, from 12hours to 32 hours, or from 18 hours to 24 hours. The resulting solidformulation may be stored at a reduced temperature, such as such asbelow 25° C., or from less than 25° C. to 0° C., from 15° C. to 0° C.,from 10° C. to 0° C., or from 7° C. to 3° C., typically at about 5° C.The solution also may be protected from light, i.e. stored in a darkenvironment, and/or stored under dry conditions, such as in the presenceof a desiccant and/or under a dry atmosphere.

C. Dosages

The pyrazole compound or combinations of pyrazole compounds willgenerally be used in an amount effective to achieve an intended result,for example, in an amount effective to treat and/or prevent a particulardisease or disorder. The pyrazole compound(s), or compositions thereof,can be administered therapeutically to achieve therapeutic benefit orprophylactically to achieve prophylactic benefit. Therapeutic benefitmeans eradication or amelioration of the underlying disorder beingtreated and/or eradication or amelioration of one or more of thesymptoms associated with the underlying disorder such that the patientreports an improvement in feeling or condition, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a compound to a patient suffering from anallergy provides therapeutic benefit not only when the underlyingallergic response is eradicated or ameliorated, but also when thepatient reports a decrease in the severity or duration of the symptomsassociated with the allergy following exposure to the allergen. Asanother example, therapeutic benefit in the context of asthma includesan improvement in respiration following the onset of an asthmatic attackor a reduction in the frequency or severity of asthmatic episodes.Therapeutic benefit also includes halting or slowing the progression ofthe disease, regardless of whether improvement is realized.

As known by those of ordinary skill in the art, the preferred dosage ofpyrazole compounds will also depend on various factors, including theage, weight, general health, and severity of the condition of thepatient or subject being treated. Dosage may also need to be tailored tothe sex of the individual and/or the lung capacity of the individual,when administered by inhalation. Dosage may also be tailored toindividuals suffering from more than one condition or those individualswho have additional conditions that affect lung capacity and the abilityto breathe normally, for example, emphysema, bronchitis, pneumonia, andrespiratory infections. Dosage, and frequency of administration of thedisclosed pyrazole compound(s) or compositions thereof, will also dependon whether the pyrazole compound(s) are formulated for treatment ofacute episodes of a condition or for the prophylactic treatment of adisorder. A person or ordinary skill in the art will be able todetermine the optimal dose for a particular individual.

For prophylactic administration, the pyrazole compound, combinations ofpyrazole compounds, or compositions thereof, can be administered to apatient or subject at risk of developing one of the previously describedconditions. For example, if it is unknown whether a patient or subjectis allergic to a particular drug, the pyrazole compound, combinations ofpyrazole compounds, or compositions thereof, can be administered priorto administration of the drug to avoid or ameliorate an allergicresponse to the drug. Alternatively, prophylactic administration can beused to avoid or ameliorate the onset of symptoms in a patient diagnosedwith the underlying disorder. For example, a pyrazole compound(s), orcomposition thereof, can be administered to an allergy sufferer prior toexpected exposure to the allergen. A pyrazole compound, combinations ofpyrazole compounds, or compositions thereof, can also be administeredprophylactically to healthy individuals who are repeatedly exposed toagents known to one of the above-described maladies to prevent the onsetof the disorder. For example, a pyrazole compound, combinations ofpyrazole compounds, or compositions thereof, can be administered to ahealthy individual who is repeatedly exposed to an allergen known toinduce allergies, such as latex, in an effort to prevent the individualfrom developing an allergy. Alternatively, a pyrazole compound,combinations of pyrazole compounds, or compositions thereof, can beadministered to a patient suffering from asthma prior to partaking inactivities which trigger asthma attacks to lessen the severity of, oravoid altogether, an asthmatic episode.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in subjects can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ or EC₅₀ of the particular compound asmeasured in an in vitro assay. Dosages can be calculated to achieve suchcirculating blood or serum concentrations taking into account thebioavailability of the particular compound. Fingl & Woodbury, “GeneralPrinciples,” In: Goodman and Gilman's The Pharmaceutical Basis ofTherapeutics, Chapter 1, pages 1-46, Pergamon Press, and the referencescited therein, provide additional guidance concerning effective dosages.

In some embodiments, the disclosed compounds have an EC₅₀ from greaterthan 0 to 20 μM, such as from greater than 0 to 10 μM, from greater than0 to 5 μM, from greater than 0 to 1 μM, from greater than 0 to 0.5 μM,or from greater than 0 to 0.1 μM.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, (1995) Allergy 50(21Suppl):6-9,discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., (2000), Arzneimittelforschung50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7.Persons of ordinary skill in the art can adapt such information todetermine dosages suitable for human administration.

Dosage amounts of disclosed pyrazole compounds will typically be in therange of from greater than 0 mg/kg/day, such as 0.0001 mg/kg/day or0.001 mg/kg/day or 0.01 mg/kg/day, up to at least 100 mg/kg/day. Moretypically, the dosage (or effective amount) may range from 0.0025 mg/kgto 1 mg/kg administered at least once per day, such as from 0.01 mg/kgto 0.5 mg/kg or from 0.05 mg/kg to 0.15 mg/kg. The total daily dosagetypically ranges from 0.1 mg/kg to 5 mg/kg or to 20 mg/kg per day, suchas from 0.5 mg/kg to 10 mg/kg per day or from 0.7 mg/kg per day to 2.5mg/kg/day. Dosage amounts can be higher or lower depending upon, amongother factors, the activity of the pyrazole compound, itsbioavailability, the mode of administration, and various factorsdiscussed above.

Dosage amount and dosage interval can be adjusted for individuals toprovide plasma levels of the pyrazole compound that are sufficient tomaintain therapeutic or prophylactic effect. For example, the compoundscan be administered once per day, multiple times per day, once per week,multiple times per week (e.g., every other day), one per month, multipletimes per month, or once per year, depending upon, amongst other things,the mode of administration, the specific indication being treated, andthe judgment of the prescribing physician. Persons of ordinary skill inthe art will be able to optimize effective local dosages without undueexperimentation.

Compositions comprising one or more of the disclosed pyrazole compoundstypically comprise from greater than 0 up to 99% of the pyrazolecompound, or compounds, and/or other therapeutic agent by total weightpercent. More typically, compositions comprising one or more of thedisclosed pyrazole compounds comprise from 1 to 20 total weight percentof the pyrazole compound and other therapeutic agent, and from 80 to 99weight percent of a pharmaceutically acceptable additive.

Preferably, the pyrazole compound, combinations of pyrazole compounds,and/or compositions thereof, will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of the pyrazolecompound can be determined using standard pharmaceutical procedures. Thedose ratio between toxic and therapeutic (or prophylactic) effect is thetherapeutic index. Pyrazole compounds that exhibit high therapeuticindices are preferred.

IV. Working Examples Example 1

Compound I-1 (8 g, 20% w/w) was slowly added to a mixture of methylenechloride (360 g) and methanol (40 g) while mixing, and the mixing wascontinued until compound I-1 dissolved. HPMCAS-MF (32 g) was then slowlyadded to the mixture while mixing, and resultant mixture was mixed untilthe HPMCAS-MF dissolved, and the solution was visually uniform. Thesolution was stored at 5° C. and protected from light.

A spray drier apparatus (Buchi B290) was prepared with a feedtemperature of 25° C., an inlet temperature of 50° C., and a targetoutlet temperature of 38° C. During the spray drying, the outlettemperature varied from 34 to 40° C., the inlet temperature varied from45 to 51° C. and the aspirator varied from 80 to 100%. The yield was 32g, 90%.

The resulting solid dispersion was collected and further dried in anoven set at 40° C. for 24 hours. The resulting powder was stored at 5°C. in the presence of a desiccant. The yield after the secondary dryingwas 27 g, 67.5%. Table 1 provides stability data for the soliddispersion.

TABLE 1 Stability data Moisture LOD, at uptake at Storage StorageStorage T_(g) 150° C. 80% RH Crystallinity Temp Config Time (° C.) (%w/w) (% w/w) by XRPD 25° C. Sealed T = 0 108.3 1.1 5.8 Amorphous T = 1m108.3 1.0 5.8 Amorphous T = 3m 108.7 1.1 5.8 Amorphous 40° C. Sealed T =0 108.3 1.1 5.8 Amorphous T = 1m — 2.0 — Amorphous T = 3m 107.5 1.2 —Amorphous Open T = 0 108.3 1.1 5.8 Amorphous T = 1m 108.4 2.7 4.9Amorphous T = 3m 108.0 1.3 — Amorphous

FIGS. 1-10 provide structural and stability data concerning thespray-dried formulation (FIGS. 1-5 ) and a crystalline sample ofcompound I-1 (FIGS. 6-10 ). FIGS. 1 and 6 provide DVS isotherm plots forthe spray-dried formulation and crystalline compound, respectively.FIGS. 1 and 6 clearly show that the crystalline compound has asubstantially smaller change in mass when exposed to higher relativehumidity than the dispersion. FIGS. 2 and 3 demonstrate that thedispersion does not have a substantially crystalline structure, whereasFIGS. 7 and 8 clearly show that the compound I-1 has a crystallinestructure.

Example 2

Two groups of male cynomolgus monkeys (n=3/group) were administered testarticles in a 3-way crossover design as indicated in Table 2. Thewashout period between doses was 3-4 days. Test article capsules wereprepared such that each capsule contained an equivalent of 25 mg of freebase compound I-1. The organic stock solution of compound I-1 wasprepared at a concentration of 5 mg/ml using TPGS/PEG400/PG, and wasdiluted with apple juice within 1 hour of dosing (PO) at 1 part stocksolution to 3 parts apple juice.

TABLE 2 Study design Dose, Corrected dose, mg of mg compound Test Testarticle compound I-1/kg, Group Phase Article Description I-1Average/(range) 1 I Capsule Phosphate 25 5.99 co-crystal II CapsuleGentisate 25 5.96 co-crystal III Capsule Spray-dried 25 5.90 Dispersion(SDD) 2 I Capsule Succinate 25 5 co-crystal II Capsule Tartrate 25 5.06co-crystal III Liquid Organic stock — 5 in apple juiceFIGS. 11-14 provide graphs of the plasma concentrations obtained fromadministering the co-crystal formulations of compound I-1 to monkeys.And Table 3 provides pharmacokinetic (PK) data for the co-crystalformulations, including the average area under the curve (AUC) andpercent bioavailability.

TABLE 3 AUC and percent bioavailability (% F) Test Average AUC_(0-24 h)± SD Article (5 mg/kg basis) % F Phosphate 921 ± 446 7.9 co-crystalSuccinate 1470 ± 1000 12.7 co-crystal Gentisate 1140 ± 811  9.8 cocystalTartrate 2860 ± 1120 24.7 co-crystal

FIG. 19 provides PK data for one embodiment of the disclosed spray-driedformulation, and the organic/juice formulation. FIG. 19 demonstratesthat administration of the spray-dried formulation resulted in 88%bioavailability of compound I-1.

Example 3

Rats were administered either compound I-1 or a potential prodrug formof compound I-1. Area under the curve (AUC) and percent bioavailability(% F) data concerning compound I-1 resulting from the prodrugadministration were determined by standard techniques known to a personof ordinary skill in the art (Table 4).

TABLE 4 AUC and percent bioavailability (% F) of compound I-1 afteradministration of potential prodrugs of I-1 Compound Dose I-1 Rat CodeProdrug Type Form equiv. AUC_(last) % F I-1 parent iv 1 mg/kg 1051 I-18alpha-methyl, 1050 30 methylene-Phosphate I-20 alpha-methyl, Disodiumsalt 3.73 mg/kg 3790 >100 methylene-Phosphate of I-18 I-45 319 10 I-46Phosphate 4510 >100 I-62 Phosphate 694 25 I-21 HCl salt of I-35, 3.68mg/kg 1850 56.6 partially crystalline I-61 Pegylated Ester 2530 103 I-32N-acetyl Free base, 3.44 mg/kg 2310 75 methylpiperazine crystalline

Example 4 Formation ofN-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamideBenzenesulfonic Acid Salt (I-65)

N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(0.050 g, 0.100 mmol, 1.0 eq) was dissolved in chloroform (1.0 eq) toobtain a clear colorless solution. Benzenesulfonic acid (0.019 g, 0.120mmol, 1.2 eq) was added and a precipitate formed over the next 15minutes. The reaction was stirred at room temperature for 1 hour and theprecipitate was isolated by filtration to obtain the title compound(0.038 g) as a white solid; ¹H nmr (400 MHz, D₆-DMSO) δ 8.53 (1H, s,thiazoleH-5 or pyrazoleH-5), 8.30 (1H, s, 1H of thiazoleH-5 orpyrazoleH-5, pyrazoleH-3, H-5), 8.29 (1H, s, 1H of thiazoleH-5 orpyrazoleH-5, pyrazoleH-3, H-5), 8.28 (1H, s, 1H of thiazoleH-5 orpyrazoleH-5, pyrazoleH-3, H-5), 8.08 (1H, dt, J 9.0, 6.5 Hz, pyridineH-4or H-5), 7.59-7.56 (2H, m, 2H of C₆H₅SO₃H), 7.32-7.27 (4H, m,pyridineH-4 or H-5, 3H of C₆H₅SO₃H), 4.33 (1H, tt, J 11.5, 3.5 Hz,cyclohexaneH-1 or H-4), 3.47 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.34 (1H, tt, J10.5, 3.5 Hz, cyclohexaneH-1 or H-4), 2.08 (4H, m, 4H of cyclohexaneH-2,H-3, H-5, H-6), 1.85 (2H, m, cyclohexaneH-2, H-3, H-5, H-6), 1.35 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz,OCH₂CH₃); ¹⁹F nmr (380 MHz, D₆-DMSO) δ −73.0 (dd, 24.5, 2.5 Hz), −124.2(ddd, J 26.0, 9.5, 1.5 Hz); m/z: 500 [M+H]⁺.

Example 5 Formation ofN-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamideSodium Salt (I-67)

N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(0.062 g, 0.124 mmol, 1.0 eq) was dissolved in chloroform (2.0 mL) toobtain a clear solution. Sodium hydroxide (0.05 mL of a 3M aqueoussolution, 0.149 mmol, 1.2 eq) was added and the reaction was stirred atroom temperature for 3 days. No precipitate was formed. The reaction wasconcentrated and further concentrated from acetonitrile (5 mL) to obtainthe title compound as a white solid; ¹H nmr (400 MHz, D₆-DMSO) δ 8.53(1H, s, thiazoleH-5 or pyrazoleH-5), 8.13 (3H, br s, thiazoleH-5 orpyrazoleH-5, pyrazoleH-3, H-5), 8.08 (1H, dt, J 9.5, 6.5 Hz, pyridineH-4or H-5), 7.28 (1H, ddd, J 9.0, 3.0, 2.5 Hz, pyridineH-4 or H-5), 4.33(1H, tt, J 11.5, 3.0 Hz, cyclohexaneH-1 or H-4), 3.47 (2H, q, J 7.0 Hz,OCH₂CH₃), 3.35 (1H, tt, J 11.0, 3.5 Hz, cyclohexaneH-1 or H-4), 2.08(4H, m, 4H of cyclohexaneH-2, H-3, H-5, H-6), 1.85 (2H, m,cyclohexaneH-2, H-3, H-5, H-6), 1.35 (2H, m, 2H of cyclohexaneH-2, H-3,H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH₂CH₃); m/z: 500 [M+H]⁺.

Example 6 Formation ofN-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamidetartaric acid cocrystal (I-66)

L-Tartaric acid (0.017 g, 0.110 mmol, 1.1 eq) was added to a solution ofN-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(0.050 g 0.100 mmol, 1.0 eq) in chloroform (1.0 eq). A white solidslowly precipitated. The reaction was stirred at room temperature for 18hours and the precipitate isolated by filtration to obtain the titlecompound (0.055 g, 85%) as a white solid; ¹H nmr (400 MHz, D₆-DMSO) δ8.53 (1H, s, thiazoleH-5 or pyrazoleH-5), 8.29 (3H, br s, thiazoleH-5 orpyrazoleH-5, pyrazoleH-3, H-5), 8.08 (1H, dt, J 9.5, 6.5 Hz, pyridineH-4or H-5), 7.28 (1H, dt, J 9.0, 3.0 Hz, pyridineH-4 or H-5), 5.05 (2H, brs, 2×OH), 4.33 (1H, tt, J 11.5, 3.5 Hz, cyclohexaneH-1 or H-4), 4.29(2H, s, COCH(OH)CH(OH)CO), 3.47 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.34 (1H,tt, J 10.5, 3.5 Hz, cyclohexaneH-1 or H-4), 2.08 (4H, m, 4H ofcyclohexaneH-2, H-3, H-5, H-6), 1.85 (2H, m, cyclohexaneH-2, H-3, H-5,H-6), 1.35 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.09 (3H, t, J7.0 Hz, OCH₂CH₃); ¹³C nmr (100 MHz, D₆-DMSO) δ 173.5, 161.7, 157.7,157.6 (d, J 236.0 Hz), 153.5 (dd, J 259.0, 4.0 Hz), 149.2, 138.2 (t, J15.0 Hz), 132.6 (d, J 9.0 Hz), 131.9 (dd, J 22.5, 9.0 Hz), 123.5, 121.5,120.2, 116.2, 109.2 (dd, J 43.0, 8.5 Hz), 76.0, 72.6, 63.0, 60.8, 30.9,30.9, 16.1; ¹⁹F nmr (380 MHz, D₆-DMSO) δ −73.0, −124.2; m/z: 500 [M+H]⁺.

Example 7 Formation ofN-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamidehemi((2R,3R)-2,3-dihydroxysuccinate) (I-11)

A MeOH (1.3 mL) solution of (L)-Tartaric Acid (750.5 mg, 5 mmol) wasadded dropwise to a CH₂Cl₂-MeOH (60 mL-5 mL) solution ofN-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(5.0 g, 10 mmol) at 35° C., additional MeOH (5 mL) and CH₂Cl₂ (100 mL)were added after 15 minutes. The mixture was stirred at 35° C. foranother 20 hours, and then cooled to room temperature. Solid wascollected by filtration, washed with CH₂Cl₂, and was further dried invacuo. The title compound was obtained as a white solid: 3.48 g (60.7%yield); ¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (br s, 1H), 12.74 (br s, 1H),11.45 (s, 1H), 8.51 (s, 1H), 8.27 (s, 1H), 8.43-8.14 (m, 2H), 8.07 (ddd,J=9.8, 8.8, 6.3 Hz, 1H), 7.27 (ddd, J=8.8, 2.9, 2.9 Hz, 1H), 5.07 (br s,1H), 4.31 (tt, partially overlapped, J=11.7, 3.2 Hz, 1H), 4.27 (s, 1H),3.45 (q, J=7.0 Hz, 2H), 3.33 (tt, partially overlapped with H₂O, J=10.7,3.6 Hz, 1H), 2.08-2.03 (m, 4H), 1.88-1.78 (m, 2H), 1.38-1.28 (m, 2H),1.08 (t, J=7.0 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −72.97 (ddd,J=28.1, 6.8, 3.8 Hz), −124.18 (ddd, J=28.1, 10.3, 3.2 Hz); LRMS (M+H)m/z 500.2.

A second crop (1.58 g, combined yield: 88%) of the same compound wasobtained from the filtrate, after removal of the solvent in vacuo, andresuspended the solid in CH₂Cl₂-MeOH (25 mL-2 mL) at 35° C. overnight.

Example 8 Preparation ofN-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(I-1)—Method 1

I. Preparation of2-bromo-N-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamideC-3 from C2·HCl

Diisopropylethylamine (8.5 mL, 48.95 mmol, 3.5 eq) was added to amixture of the aminopyrazole C-2·HCl (5.00 g, 13.99 mmol, 1.0 eq) andbromothiazolecarboxylic acid (3.20 g, 15.38 mmol, 1.1 eq) indichloromethane (50 mL) at 0° C. HATU (5.85 g, 15.38 mmol, 1.1 eq)added. The reaction was stirred at 0° C. for 10 minutes and then at roomtemperature for 4 hours. The reaction was diluted with CH₂Cl₂ (100 mL).The organics were washed with NaHCO₃ (150 mL), NH₄Cl (150 mL) and brine(100 mL), dried (Na₂SO₄) and concentrated under reduced pressure. Theresidue was suspended in EtOAc-hexane (1:1, 50 mL) and the resultingsolid was isolated by filtration. The solid was suspended in NaHCO₃ (50mL) for 1 hour to remove residual coupling agent before isolating byfiltration and drying under vacuum to obtain C-3 (5.3 g, 74%) as anoff-white solid; IR ν_(max) (film) 3290, 3121, 2942, 2865, 1671, 1615,1552, 1485, 1431, 1377, 1237, 1154, 1104, 1056, 1011, 819, 787, 731cm⁻¹; ¹H nmr (400 MHz, CDCl₃) δ 8.42 (1H, d, J 0.5 Hz, thiazoleH-5 orpyrazoleH-5), 8.09 (1H, s, thiazoleH-5 or pyrazoleH-5), 7.63 (1H, td, J9.0, 6.0 Hz, pyridineH-4 or H-5), 6.85 (1H, ddd, J 9.0, 3.5, 2.5 Hz,pyridineH-4 or H-5), 4.26 (1H, tt, J 11.5, 4.0 Hz, cyclohexaneH-1 orH-4), 3.55 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.36 (1H, tt, J 10.5, 4.0 Hz,cyclohexaneH-1 or H-4), 2.28 (2H, br d, J 13.0 Hz, 2H of cyclohexaneH-2,H-3, H-5, H-6), 2.21 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.91,1.84 (2H, 2dd AB system, J 13.0, 3.5 Hz, 2H of cyclohexaneH-2, H-3, H-5,H-6), 1.46 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.22 (3H, t, J7.0 Hz, OCH₂CH₃); ¹³C nmr (100 MHz, CDCl₃) δ 157.6 (d, J 238.0 Hz),156.9, 153.3 (dd, J 260.0, 8.5 Hz), 150.0, 138.6 (t, J 14.0 Hz), 136.1,133.1 (d, J 8.5 Hz), 129.8 (dd, J 23.0, 8.5 Hz), 126.7, 121.7, 119.2,107.8 (dd, J 39.5, 5.5 Hz), 76.4, 63.6, 61.5, 31.1, 30.9, 15.7; ¹⁹F nmr(380 MHz, CDCl₃) δ −72.3, −124.9; m/z: 536, 534 [M+Na]⁺, 514, 512[M+H]⁺. The filtrate from the initial trituration was purified by columnchromatography (20→80% EtOAc-hexane) to obtain further C-3 (0.8 g, 9%)as a pink foam.

II. Preparation ofN-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(I-1)

Dioxane (400 mL) was added to a mixture of the bromothiazole C-3 (25.0g, 48.8 mmol, 1.0 eq) and pyrazole-4-boronic acid (8.2 g, 73.2 mmol, 1.5eq) followed by aqueous solution of sodium carbonate (73.3 mL of a 2Msolution, 146.5 mmol, 3.0 eq). The reaction mixture was degassed bybubbling argon through for five minutes.

Tetrakis(triphenylphosphine)palladium (1.4 g, 1.2 mmol, 0.025 eq) wasadded and the reaction further degassed before heating to 105° C. for 6hours. The reaction was filtered through Celite® while hot, eluting withEtOAc (200 mL). The filtrate was concentrated to approximately 150 mL,upon which a precipitate formed. The precipitate was isolated byfiltration. The filtrate was concentrated to remove the remainingorganics, filtered to remove more precipitate, diluted with water-brine(1:2, 300 mL) and extracted with EtOAc (3×200 mL). The combined organicswere combined, dried (Na₂SO₄) and concentrated under reduced pressure.The combined precipitates and extracts were loaded onto silica. Columnchromatography (silica, 0→10% MeOH—CH₂Cl₂) yielded the title compound(16.5 g, 68%) as a white solid; IR ν_(max)(film) 3229, 2938, 2861, 1663,1615, 1589, 1549, 1482, 1425, 1377, 1237, 1104, 1055, 972, 930, 903,875, 820, 786, 715, 664 cm⁻¹; ¹H nmr (400 MHz, CDCl₃) δ 8.52 (1H, s,thiazoleH-5 or pyrazoleH-5), 8.24 (2H, s, NHpyrazoleH-3, H-5), 8.07 (1H,s, thiazoleH-5 or pyrazoleH-5), 7.41 (1H, td, J 9.0, 6.0 Hz, pyridineH-4or H-5), 6.86 (1H, ddd, J 9.0, 3.5, 2.5 Hz, pyridineH-4 or H-5), 4.28(1H, tt, J 11.5, 4.0 Hz, cyclohexaneH-1 or H-4), 3.57 (2H, q, J 7.0 Hz,OCH₂CH₃), 3.37 (1H, tt, J 11.0, 4.0 Hz, cyclohexaneH-1 or H-4), 2.26(4H, m, 4H of cyclohexaneH-2, H-3, H-5, H-6), 1.92, 1.86 (2H, 2dd ABsystem, J 13.0, 3.5 Hz, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.50, 1.44(2H, 2dd AB system, J 13.0, 3.5 Hz, 2H of cyclohexaneH-2, H-3, H-5,H-6), 1.23 (3H, t, J 7.0 Hz, OCH₂CH₃); ¹³C nmr (100 MHz, CDCl₃) δ 160.6,158.6, 158.3, 156.3, 154.8, 152.2, 150.2, 138.9, 133.0 (d, J 9.0 Hz),129.9 (dd, J 23.5, 9.0 Hz), 122.0, 121.6, 119.4, 117.2, 107.5 (dd, J40.5, 5.0 Hz), 76.4, 63.7, 61.5, 31.1, 30.9, 15.7; ¹⁹F nmr (380 MHz,CDCl₃) δ −72.7 (dddd, J 27.0, 9.5, 5.5, 4.0 Hz), −124.3 (ddd, J 27.5,9.5, 3.0 Hz); m/z: 500 [M+H]⁺ (found [M+H]⁺, 500.1687, C₂₃H₂₃F₂N₇O₂Srequires [M+H]⁺ 500.1675).

Example 9 Preparation ofN-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(I-1)—Method 2

I. Formation of 2-(1H-pyrazol-4-yl)thiazole-4-carboxylic acid

A 1,4-Dioxane-H₂O (32 mL-8 mL) solution of 2-bromothiazole-4-carboxylicacid (2.08 g, 10 mmol, 1.0 eq), (1H-pyrazol-4-yl)boronic acid (3.36 g,30 mmol, 3.0 eq), tetrakis(triphenylphosphine)palladium (0.23 g, 0.2mmol, 0.02 eq) and sodium carbonate (3.18 g, 30 mmol, 3.0 eq) wasdegassed, backed-filled with nitrogen gas, three times. The cloudysolution was stirred at 60° C. for 2 hours (by LC-MS, startingmaterial:product≈1:1), then at 100° C. for a further 3 hours, until thereaction went to completion as monitored by LC-MS. After removal oforganic solvent under reduced pressure, the crude mixture was dilutedwith water (100 mL) and mixed well. The aqueous solution was passedthrough a Celite® pad, and washed with water. While stirring, thefiltrate with acidified with 6M HCl aq. solution (about 11 mL) untilpH=1-2. The precipitate was collected by filtration, washed with waterand further dried in vacuo to obtain the title compound (1.79 g 92%yield) as a light tan color solid; ¹H nmr (400 MHz, D₆-DMSO) δ 13.11(2H, br s, NH, OH), 8.28 (1H, s, thiazoleH-4), 8.17 (2H, br s,pyrazoleH-3, H-5); m/z: 196 [M+H]⁺.

II. Preparation ofN-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(I-1)

A mixture of the C2·HCl aminopyrazole hydrochloride (1.00 g, 2.80 mmol,1.0 eq) and 2-(1H-pyrazol-4-yl)thiazole-4-carboxylic acid (0.65 g, 3.36mmol, 1.2 eq) in dimethylformamide (14 mL) was cooled to 0° C. anddiisopropylethylamine (1.22 mL, 6.99 mmol, 2.5 eq) added. A solutionresulted to which was added HATU (1.17 g, 3.08 mmol, 1.1 eq). Thesolution was stirred at 0° C. for 15 minutes and room temperature for 1hour, before adding the reaction to water (75 mL). A solid formed thatcollapsed to a gum. The liquid was decanted isolating any solid byfiltration. The gum and solid were dissolved in EtOAc-MeOH (4:1, 100mL), combined and concentrated under reduced pressure. The resultingsolid was triturated from 10% EtOH-EtOAc (4 mL) to obtain the titlecompound I-1 as an off-white solid (0.76 g, 55%). The filtrate wasconcentrated and loaded onto silica. Column chromatography (0→10%MeOH—CH₂Cl₂) yielded a pale yellow solid, which was stirred with NaHCO₃(15 mL). The liquid was decanted and the residue triturated with 10%EtOH-EtOAc (4 mL) to obtain further product as an off-white solid (0.226g, 16%). Total yield 0.99 g, 71%; data agreed with that stated above.

Example 10 Exemplary Synthesis of Alkyl Phosphate Compounds

I. Preparation of Di-tert-butyl((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphate (I-3)

Potassium carbonate (0.41 g, 3.01 mmol, 1.5 eq) was added to asuspension of I-1 (1.00 g, 2.00 mmol, 1.0 eq) in dimethylformamide (14mL). The reaction was stirred at room temperature for 30 minutes beforeadding a solution of chloromethyl di-tert-butyl phosphate (1.04 g, 4.01mmol, 2.0 eq) in dimethylformamide (2 mL). The reaction was stirred atroom temperature for 14 hours. Further chloromethyl di-tert-butylphosphate (0.52 g, 2.00 mmol, 1.0 eq) and potassium carbonate (0.21 g,1.50 mmol, 0.75 eq) was added and the reaction stirred for a further 24hours. The reaction was cooled to 0° C. and water (25 mL) added dropwiseover 45 minutes. A sticky solid resulted which was isolated by decantingthe liquid. The liquid was added to water (40 mL) and stirred to obtainmore solid, which was isolated by filtration. The solid was dried undervacuum and used without further purification (1.76 g,quantitative-theoretical yield 1.44 g); IR ν_(max) (film) 3308, 2979,2978, 2864, 1668, 1615, 1592, 1549, 1482, 1374, 1266, 1234, 1104, 998,965, 822, 787, 714, 666 cm⁻¹; ¹H nmr (400 MHz, CDCl₃) δ 8.50 (1H, s,pyrazoleH-5, thiazoleH-5), 8.34 (1H, s, 1H of pyrazoleH-3, H-5), 8.21(1H, s, 1H of pyrazoleH-3, H-5), 8.06 (1H, s 1H of pyrazoleH-5,thiazoleH-5), 7.65 (1H, td, J 9.0, 6.0 Hz, pyridineH-4 or H-5), 6.88(1H, ddd, J 9.0, 3.0, 2.5 Hz, pyridineH-4 or H-5), 5.93 (2H, d, J 12.5Hz, NCH₂OP), 4.27 (1H, tt, J 12.0, 4.0 Hz, cyclohexaneH-1 or H-4), 3.56(2H, q, J 7.0 Hz, OCH₂CH₃), 3.37 (1H, tt, J 10.5, 4.0 Hz, cyclohexaneH-1or H-4), 2.29 (2H, br d, J 12.5 Hz, 2H of cyclohexaneH-2, H-3, H-5,H-6), 2.22 (2H, br d, J 11.0 Hz, 2H of cyclohexaneH-2, H-3, H-5, H-6),1.89 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.50 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.45 (18H, s, 2×OC(CH₃)₃), 1.22 (3H, t,J 7.0 Hz, OCH₂CH₃); ¹³C nmr (100 MHz, CDCl₃) δ 160.0, 158.2, 157.5 (d, J236.5 Hz), 153.5 (dd, J 260.0, 5.0 Hz), 150.2, 139.5 (d, J 6.0 Hz),138.9 (t, J 15.0 Hz), 133.0 (d, J 9.0 Hz), 130.0 (d, J 4.5 Hz), 129.8(d, J 9.0 Hz), 122.0, 121.8, 119.4, 118.6, 107.6 (dd, J 40.5, 5.0 Hz),83.9, 83.8, 77.2, 76.4, 63.6, 61.5, 31.1, 30.9, 29.8, 29.7, 15.7; ³¹Pnmr (162 MHz, CDCl₃) δ −11.1; ¹⁹F nmr (380 MHz, CDCl₃) δ −72.4 (dt, J27.0, 5.5 Hz), −124.5 (dd, J 27.5, 9.5 Hz); m/z: 744 [M+Na]⁺.

II. Preparation of(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate (I-2)

To a solution of I-3 (1.58 g crude mass, 1.80 mmol, 1.0 eq) indichloromethane (8.0 mL) was added trifluoroacetic acid (0.99 mL, 12.80mmol, 7.1 eq). The reaction was stirred at room temperature for 20hours, during which time a precipitate formed. After 20 hours theprecipitate was isolated by filtration. The solid was washed with CH₂Cl₂(2×8 mL) to obtain a white solid. The solid was stirred withdioxane-water (10:1, 11 mL) for 5 hours and filtered, washing withdioxane-water (10:1, 11 mL) to obtain I-2 (0.60 g, 55% over two steps)as a white solid. The filtrate was concentrated and stirred indioxane-water (10:1, 11 mL) for 18 hours before isolating by filtration.The solid was washed with dioxane-water (10:1, 2×5.5 mL) to obtainfurther product (0.12 g, total 0.72 g, 66%) as a white solid; ¹H nmr(400 MHz, D₆-DMSO) δ 8.59 (1H, s, 1H of pyrazoleH-3, H-5), 8.52 (1H, s,1H of pyrazoleH-3, H-5), 8.34 (1H, s, 1H of pyrazoleH-5, thiazoleH-5),8.19 (1H, s, 1H of pyrazoleH-5, thiazoleH-5), 8.08 (1H, td, J 9.5, 6.5Hz, pyridineH-4 or H-5), 6.88 (1H, ddd, J 9.0, 3.0, 2.5 Hz, pyridineH-4or H-5), 5.83 (2H, d, J 12.5 Hz, NCH₂OP), 4.33 (1H, tt, J 12.0, 3.0 Hz,cyclohexaneH-1 or H-4), 3.47 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.35 (1H, tt, J10.5, 3.5 Hz, cyclohexaneH-1 or H-4), 2.29 (4H, br d, J 11.0 Hz, 4H ofcyclohexaneH-2, H-3, H-5, H-6), 1.85 (2H, m, 2H of cyclohexaneH-2, H-3,H-5, H-6), 1.35 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H,t, J 7.0 Hz, OCH₂CH₃); ¹³C nmr (100 MHz, CDCl₃) δ 160.6, 157.6, 157.6(d, J 234.5 Hz), 154.3 (dd, J 259.5, 4.0 Hz), 149.4, 137.7 (d, J 7.0Hz), 138.2, 132.6 (d, J 9.0 Hz), 131.9 (dd, J 22.0, 9.0 Hz), 131.4,124.1, 121.4, 120.2, 117.7, 109.2 (d, 38.0 Hz), 76.0, 75.2, 63.0, 60.8,30.9 (2C), 16.1; ³¹P nmr (162 MHz, D₆-DMSO) δ −2.7; ¹⁹F nmr (380 MHz,D₆-DMSO) δ −72.8, −124.2 (ddd, J 27.0, 9.5, 3.0 Hz); m/z: 610 [M+H]⁺(found [M+H]⁺, 610.1451, C₂₄H₂₆F₂N₇O₆PS requires [M+H]⁺ 610.1444).

Other phosphate compounds were made by similar methods

Example 11 Exemplary Synthesis of Carbamates and Ureas as Potential IRAKProDrugs I. Formation of 2-morpholinoethyl (4-nitrophenyl) carbonate

A solution of 4-nitrophenol chloroformate (0.500 g, 2.48 mmol, 1.0 eq)in dichloromethane (20 mL) was cooled to −78° C. Diisopropylethylamine(0.65 mL, 3.72 mmol, 1.5 eq) was added followed by4-(2-hydroxyethyl)morpholine (0.30 mL, 2.48 mmol, 1.0 eq) and thereaction was stirred between −78° C. and room temperature over 16 hours.The reaction was diluted with dichloromethane (40 mL) and washed withNaHCO₃ (60 mL) and brine (60 mL), dried (Na₂SO₄) and concentrated underreduced pressure to obtain the title compound as an orange oil; ¹H nmr(400 MHz, CDCl₃) δ 8.27 (2H, d, J 9.5 Hz, 2H of C₆H₄NO₂), 7.37 (2H, d, J9.0 Hz, 2H of C₆H₄NO₂), 4.39 (2H, t, J 5.5 Hz, 2H of COOCH₂CH₂N), 3.72,3.71 (4H, 2d AB system, J 4.5 Hz, 4H of morpholine), 2.72 (2H, t, J 5.5Hz, 2H of COCH₂CH₂N), 2.54, 2.53 (4H, 2d AB system, J 4.5 Hz, 4H ofmorpholine).

II. Formation of 3-morpholinopropyl (4-nitrophenyl) carbonate

Diisopropylethylamine (0.65 mL, 3.72 mmol, 1.5 eq) was added to asolution of 4-nitrophenyl chloroformate (0.500 g, 2.48 mmol, 1.0 eq) indichloromethane (20 mL) at −78° C. 3-(Hydroxypropyl)morpholine (0.34 mL,2.48 mmol, 1.0 eq) was added dropwise and the reaction stirred at −78°C. for 30 minutes. The reaction froze and was warmed to 0° C. Afterstirred at 0° C. for 5 hours the reaction was allowed to warm to roomtemperature over 16 hours. The reaction was diluted with dichloromethane(20 mL) and washed with NaHCO₃ (3×40 mL). The organics were dried(Na₂SO₄) and concentrated under reduced pressure to obtain the titlecompound as a pale yellow oil; ¹H nmr (400 MHz, CDCl₃) δ 8.26 (2H, d, J9.5 Hz, 2H of C₆H₄NO₂), 7.36 (2H, d, J 9.0 Hz, 2H of C₆H₄NO₂), 4.36 (2H,t, J 6.5 Hz, OCH₂CH₂CH₂N), 3.70 3.69 (4H, 2d AB system, J 4.5 Hz, 4H ofmorpholine), 2.49-2.43 (6H, m, 4H of morpholine, OCH₂CH₂CH₂N), 1.93(pentet, J 6.5 Hz, OCH₂CH₂CH₂N).

III. Formation of 2-morpholinoethyl4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate(I-10)

To the nitrophenyl carbonate (0.050 g, 0.169 mmol, 1.5 eq) indichloromethane (1.0 mL) at 0° C. was addedN-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(0.056 g, 0.113 mmol, 1.0 eq) and dimethylaminopyridine (0.001 g, 0.011mmol, 0.1 eq). Triethylamine (0.023 mL, 0.169 mmol, 1.5 eq) was addedand the reaction stirred at 0° C. for 30 minutes and room temperaturefor 1 hour. The reaction was partitioned between CH₂Cl₂ (30 mL) andNaHCO₃ (30 mL). The aqueous phase was extracted with CH₂Cl₂ (2×30 mL).The combined organics were dried (Na₂SO₄) and concentrated under reducedpressure. MPLC (20→80% acetone-hexane, 0.1% triethylamine) yielded thetitle compound as a white solid; ¹H nmr (400 MHz, CDCl₃) δ 8.75 (1H, s,1H of thiazoleH-5, pyrazoleH-5, pyrazoleH-3, H-5), 8.49 (1H, s, 1H ofthiazoleH-5, pyrazoleH-5, pyrazoleH-3, H-5), 8.35 (1H, s, 1H ofthiazoleH-5, pyrazoleH-5, pyrazoleH-3, H-5), 8.13 (1H, s, 1H ofthiazoleH-5, pyrazoleH-5, pyrazoleH-3, H-5), 7.64 (1H, td, J 9.0, 6.0Hz, pyridineH-4 or H-5), 6.86 (1H, dt, J 8.5, 3.5, 2.5 Hz, pyridineH-4or H-5), 4.63 (2H, t, J 6.0 Hz, COOCH ₂CH₂N), 4.26 (1H, tt, J 11.5, 4.0Hz, cyclohexaneH-1 or H-4), 3.70, 3.68 (4H, 2d AB system, J 4.5 Hz, 4Hof morpholine), 3.55 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.36 (1H, tt, J 10.5,4.0 Hz, cyclohexaneH-1 or H-4), 2.84 (2H, t, J 6.0 Hz, COOCH₂CH ₂N),2.58, 2.57 (4H, 2d AB system, J 4.5 Hz, 4H of morpholine), 2.28 (2H, m,2H of cyclohexaneH-2, H-3, H-5, H-6), 2.20 (2H, m, 2H of cyclohexaneH-2,H-3, H-5, H-6), 1.88 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.45(2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.21 (3H, t, J 7.0 Hz,OCH₂CH ₃); ¹⁹F nmr (380 MHz, CDCl₃) δ −72.7 (ddd, J 27.0, 5.5, 4.0 Hz),−124.3 (ddd, 27.0, 11.0, 9.5 Hz); m/z: 657 [M+H]⁺.

IV. Formation of 3-morpholinopropyl4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate(I-15)

To a mixture of the nitrophenyl carbonate (0.068 g, 0.220 mmol, 1.1 eq)andN-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(0.100 g, 0.200 mmol, 1.0 eq) in dichloromethane (2.0 mL) at 0° C. wasadded triethylamine (0.031 mL, 0.220 mmol, 1.1 eq) anddimethylaminopyridine (0.002 g, 0.020 mmol, 0.1 eq). The reactionstirred at 0° C. for 1 hour and then at room temperature for 3 hours,resulting an almost clear solution. The reaction was partitioned betweenCH₂Cl₂ (30 mL) and NaHCO₃ (30 mL). The aqueous phase was extracted withCH₂Cl₂ (2×30 mL). The combined organics were dried (Na₂SO₄) andconcentrated under reduced pressure. MPLC (40→100% acetone-hexane, 0.1%triethylamine) yielded the title compound (0.077 g, 57%) as a whitesolid; ¹H nmr (400 MHz, CDCl₃) δ 8.75 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.49 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3or H-5), 8.34 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5),8.12 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 7.64 (1H,td, J 9.0, 6.0 Hz, pyridineH-4 or H-5), 6.87 (1H, ddd, J 9.0, 3.5, 2.5Hz, pyridineH-4 or H-5), 4.61 (2H, 6.5 Hz, 2H of OCH ₂CH ₂CH₂N), 4.26(1H, tt, J 11.5, 4.0 Hz, cyclohexaneH-1 or H-4), 3.66, 3.65 (4H, 2d ABsystem, J 4.5 Hz, 4H of morpholine), 3.55 (2H, q, J 7.0 Hz, OCH ₂CH₃),3.35 (1H, tt, J 10.5, 4.0 Hz, cyclohexaneH-1 or H-4), 2.52 (2H, J 7.0Hz, 2H of OCH ₂CH₂CH ₂N), 2.44 (4H, m, 4H of morpholine), 2.30-2.24 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.24-2.17 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 2.05 (2H, pentet, J 6.5 Hz, OCH₂CH₂CH₂N), 1.93-1.83 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6),1.51-1.41 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.21 (3H, t, J7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, CDCl₃) δ −72.7 (ddd, J 28.5, 5.5,4.0 Hz), −124.3 (ddd, J 28.0, 9.5, 2.5 Hz); m/z: 671 [M+H]⁺ (found[M+H]⁺, 671.2560, C₃₁H₃₆F₂N₈O₅S requires [M+H]⁺ 671.2570).

A person of ordinary skill in the art will understand that the abovemethods also can be used to make the corresponding urea compounds, suchas I-13 and I-14, by using an amine in place of the starting hydroxycompound. An exemplary scheme to synthesis urea compound I-13 isprovided below.

Example 12 Exemplary Synthesis of Amino Acid Esters Synthesis of(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylL-valinate hydrochloride (I-16)

I. Preparation of Chloromethyl (tert-butoxycarbonyl)-L-valinate

To a solution of N-Boc-valine (5.00 g, 23.0 mmol, 1.0 eq) indichloromethane (100 mL) was added sodium bicarbonate (7.74 g, 92.2mmol, 4.0 eq) and tetrabutylammonium hydrogen sulfate (0.78 g, 2.3 mmol,0.1 eq) followed by water (100 mL). The mixture was stirred for 10minutes to allow for dissolution before cooling to 0° C. and adding asolution of chloromethyl chlorosulfate (3.0 mL, 29.0 mmol, 1.3 eq) indichloromethane (20 mL) dropwise over 20 minutes. The reaction wasstirred at 0° C. for 1 hour and then at room temperature for 18 hours.The reaction was partitioned and the aqueous phase was extracted withCH₂Cl₂ (20 mL). The combined organic phases were washed with water(3×100 mL) and brine (100 mL), dried (Na₂SO₄) and concentrated underreduced pressure to obtain the title compound (6.10 g, quantitative) asa colourless oil; ¹H nmr (400 MHz, CDCl₃) δ 5.87 (1H, d, J 6.0 Hz, 1H ofOCH₂Cl), 5.61 (1H, d, J 6.0 Hz, 1H of OCH₂Cl), 4.97 (1H, br d, J 7.0 Hz,NH), 4.27 (1H, dd, J 9.0, 4.5 Hz, COCHNH), 2.22-2.17 (1H, m,CHCH(CH₃)₂), 1.44 (9H, s, C(CH₃)₃), 0.99 (3H, d, J 6.5 Hz, 1×CH₃ ofCH(CH₃)₂), 0.92 (3H, d, J 7.0 Hz, 1×CH₃ of CH(CH₃)₂).

II. Preparation of(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl(tert-butoxycarbonyl)-L-valinate

To a mixture of I-1 (5.00 g, 10.0 mmol, 1.0 eq) and N-Boc-valinechloromethyl ester (2.93 g, 11.0 mmol, 1.1 eq) was addeddimethylformamide (50 mL). Caesium carbonate (3.92 g, 12.0 mmol, 1.2 eq)was added and the reaction stirred at room temperature for 16 hours. Thereaction was partitioned between EtOAc (150 mL) and water (150 mL). Theorganics were washed with brine (100 mL). The combined organics wereback-extracted with EtOAc (75 mL). The combined organics were washedwith water (200 mL) and brine (150 mL), dried (Na₂SO₄) and concentratedunder reduced pressure. MPLC (50→100% EtOAc-hexane) yielded the titlecompound (6.51 g, 89%) as a white solid; ¹H nmr (400 MHz, CDCl₃) δ 8.48(1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.29 (1H, s,pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.14 (1H, s, pyrazoleH-5,thiazoleH-5, pyrazoleH-3 or H-5), 8.04 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 7.63 (1H, td, J 9.0, 6.0 Hz, pyridineH-4 or H-5),6.87 (1H, ddd, J 9.0, 3.5, 2.5 Hz, pyridineH-4 or H-5), 6.21, 6.02 (2H,2d AB system, J 10.5 Hz, NCH₂O), 4.94 (1H, d, J 9.0 Hz, NHBoc),4.28-4.21 (2H, m, cyclohexaneH-1 or H-4, COCHNH), 3.54 (2H, q, J 7.0 Hz,OCH ₂CH₃), 3.43 (1H, tt, J 10.5, 4.0 Hz, cyclohexaneH-1 or H-4),2.30-2.24 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.23-2.16 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.13-2.04 (1H, m, CHCH(CH₃)₂),1.92-1.82 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.49-1.40 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.40 (9H, s, C(CH₃)₃), 1.20(3H, t, J 7.0 Hz, OCH₂CH ₃), 0.86 (3H, d, J 6.5 Hz, 1×CH₃ of CH(CH ₃)₂),0.77 (3H, d, J 6.5 Hz, 1×CH₃ of CH(CH ₃)₂); ¹³C nmr (100 MHz, CDCl₃) δ171.9, 159.7, 158.2, 15× (d, J 236.5 Hz), 155.6, 153.x (dd, J 260.5, 4.5Hz), 150.2, 139.8 (d, J 5.0 Hz), 138.9 (t, J 14.5 Hz), 133.0 (d, J 8.5Hz), 130.5 (d, J 5.0 Hz), 129.9 (dd, J 22.5, 9.0 Hz), 122.0, 121.8,119.4, 118.6, 107.6 (dd, J 40.5, 5.5 Hz), 80.1, 77.2, 76.4, 72.6, 63.6,61.5, 58.4, 31.1, 31.0, 30.9, 28.3, 18.8, 17.4, 15.7; ¹⁹F nmr (380 MHz,CDCl₃) δ −72.6, −124.4; m/z: 751 [M+H]⁺, 673 [M+H—C₄H₈]⁺, 629[M+H—C₄H₈—CO₂]⁺.

III. Preparation of(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylL-valinate hydrochloride, 1-16

To a solution/suspension of the Boc-protected valine methylene ester(1.73 g, 2.38 mmol, 1.0 eq) in ethyl acetate (25 mL) was added hydrogenchloride 5.94 mL of a 4M solution in dioxane, 23.76 mmol, 10.0 eq). Thereaction was stirred at room temperature for 18 hours. Further hydrogenchloride 3.0 mL of a 4M solution in dioxane, 11.88 mmol, 5.0 eq) wasadded and the reaction stirred for a further 8 hours beforeconcentrating under reduced pressure. The residue was concentrated fromEtOAc (2×30 ml) and dried under vacuum to yield the title compound (1.50g, quantitative) as a white solid; ¹H nmr (400 MHz, D₆-DMSO) δ 8.66 (1H,s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.51 (1H, s,pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.35 (1H, s, pyrazoleH-5,thiazoleH-5, pyrazoleH-3 or H-5), 8.22 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.07 (1H, td, J 9.0, 6.0 Hz, pyridineH-4 or H-5),7.25 (1H, ddd, J 8.5, 3.0, 2.5 Hz, pyridineH-4 or H-5), 6.2×, 6.2× (2d,AB system, J Hz, NCH₂OCO), 4.32 (1H, tt, J 11.5, 3.0 Hz, cyclohexaneH-1or H-4), 3.90 (1H, d, J 4.0 Hz, COCHNH₂), 3.45 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.30 (1H, tt, J 11.0, 4.0 Hz, cyclohexaneH-1 or H-4), 2.12-2.00(5H, m, 4H of cyclohexaneH-2, H-3, H-5, H-6, CH(CH₃)₂), 1.88-1.80 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.38-1.29 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.08 (3H, t, J 7.0 Hz, OCH₂CH ₃), 0.87(3H, d, J 7.0 Hz, 3H of CH(CH ₃)₂), 0.83 (3H, d, J 7.0 Hz, 3H of CH(CH₃)₂); ¹⁹F nmr (380 MHz, D₆-DMSO) δ −73.0 (d, J 28.5 Hz), −124.1 (dd, J27.0, 9.5 Hz); m/z: 629 [M+H]⁺ (found [M+H]⁺, 629.2477, C₂₉H₃₄F₂N₈O₄Srequires [M+H]⁺ 629.2465).

A person of ordinary skill in the art will understand that this methodis generally applicable to any amino acid, particularly a naturallyoccurring amino acid, as disclosed herein.

Example 13 Synthesis of1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyldihydrogen phosphate (I-18)

I. Preparation of Chloroethyl Chlorosulfate

Chlorosulfonic acid (4.90 mL, 73.7 mmol, 1.46 eq) was added dropwise tochloroethyl chloroformate (5.44 mL, 50.4 mmol, 1.0 eq) at 0° C. over 20minutes. The reaction was stirred at 0° C. for 2 hours and then at roomtemperature for 10 minutes (during which time the solution temperaturerose to 5° C.). Dichloromethane (50 mL) was added followed carefully byice (2 g), and the mixture stirred rapidly to ensure mixing. Somebubbling was observed and the yellow solution became green-black. Themixture was washed with NaHCO₃ (2×40 mL) to ensure the organics are notacidic. The organics were washed with brine (40 mL), dried (Na₂SO₄) toobtain a clear solution, which was concentrated under reduced pressureto obtain the title compound (4.72 g, 52%) as a black-brown oil; ¹H nmr(400 MHz, CDCl₃) δ 6.46 (1H, q, J 6.0 Hz, ClCH(CH₃)O), 1.97 (3H, d, J5.5 Hz, CHCH ₃).

II. Synthesis of 1-chloroethyl di-tert-butyl phosphate

Potassium di-tert-butyl phosphate (5.44 g, 21.97 mmol, 1.0 eq) wasdissolved in dichloromethane-water (200 mL, 1:1) and cooled to 0° C.Sodium bicarbonate (7.37 g, 87.74 mmol, 4.0 eq) and tetrabutylammoniumhydrogen phosphate (0.74 g, 2.19 mmol, 0.1 eq) were added and thereaction was stirred at 0° C. for 10 minutes. Chloroethyl chlorosulfate(4.72 g as a solution in 20 mL of dichloromethane, 26.37 mmol, 1.2 eq)was then added dropwise over 30 minutes at 0° C. The resulting mixturewas stirred rapidly at room temperature for 18 hours and partitioned.The organics were washed with water (3×100 mL) and brine (100 mL), dried(Na₂SO₄) and concentrated under reduced pressure to obtain the titlecompound (2.35 g, 39%) as a pale brown oil; ¹H nmr (400 MHz, CDCl₃) δ6.19 (1H, dq, J 8.5, 5.5 Hz, ClCH(CH₃)O), 1.79 (3H, dd, J 5.5, 1.0 Hz,CHCH ₃), 1.49 (9H, s, 1×OC(CH₃)₃), 1.48 (9H, s, 1×OC(CH₃)₃); ³²P nmr(380 MHz, CDCl₃) δ −13.0.

III. Preparation of Di-tert-butyl(1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl)phosphate

To a suspension of I-1 (2.00 g, 4.01 mmol, 1.0 eq) in degasseddimethylformamide (15 mL) was added potassium iodide (0.07 g, 0.40 mmol,0.1 eq) and potassium hydroxide (0.90 g, 16.03 mmol, 4.0 eq) as smallflakes. Chloroethyl di-tert-butyl phosphate (1.64 g as a solution in 5mL of dimethylformamide, 6.01 mmol, 1.5 eq) was added dropwise over 10minutes. The resulting mixture was heated to 50° C. for 14 hours beforecooling and diluting with EtOAc (50 mL). The reaction was partitionedbetween EtOAc (100 mL) and water (150 mL). The organics were washed withbrine (100 mL), water (150 mL) and brine (100 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. Column chromatography (silica,50→100% EtOAc-hexane) yielded the title compound as a white solid; ¹Hnmr (400 MHz, CDCl₃) δ 11.73 (1H, s, NH), 8.51 (1H, s, pyrazoleH-5,thiazoleH-5, pyrazoleH-3 or H-5), 8.33 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.16 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3or H-5), 8.05 (1H, s pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 7.65(1H, td, J 9.0, 6.5 Hz, pyridineH-4 or H-5), 6.88 (1H, ddd, J 8.0, 3.0,2.5 Hz, pyridineH-4 or H-5), 6.39 (1H, dq, J 7.5, 6.5 Hz, NCH(CH₃)O),4.27 (1H, tt, J 11.5, 3.5 Hz, cyclohexaneH-1 or H-4), 3.56 (2H, q, J 7.0Hz, OCH ₂CH₃), 3.37 (1H, tt, J 10.5, 4.5 Hz, cyclohexaneH-1 or H-4),2.32-2.26 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.26-1.90 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.94 (3H, d, J 6.5 Hz, NCH(CH₃)O), 1.93-1.84 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.52-1.42(11H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6, 1×C(CH₃)₃), 1.37 (9H, s,1×C(CH₃)₃), 1.23 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, CDCl₃) δ−72.3, −124.5; ³²P nmr (380 MHz, CDCl₃) δ −11.9; m/z: 758 [M+Na]⁺.

Alternative Synthesis of Di-tert-butyl(1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl)phosphate

To a mixture of I-1 (7.00 g, 14.0 mmol, 1.0 eq) and potassium iodide(0.23 g, 1.4 mmol, 0.1 eq) was added dioxane (48 mL) followed by cesiumcarbonate (9.15 g, 28.1 mmol, 2.0 eq). The resulting suspension wasstirred at room temperature and chloroethyl di-tert-butyl phosphate(4.20 g as a solution in 8 mL of dioxane, 15.4 mmol, 1.1 eq) was added.The reaction was heated to 70° C. for 30 hours before cooling andpartitioning between EtOAc (100 mL) and NH₄Cl-water (1:1, 100 mL). Theorganics were dried (Na₂SO₄) and concentrated under reduced pressure. Onstanding in the fridge a solid formed along with some liquid thought tobe water. The liquid did not contain any product and was decanted. EtOAc(7.5 mL) was added and the solid isolated by filtration, washing withEtOAc (7.5 mL and 5 mL). The solid was dried under vacuum to obtain thetitle compound (5.20 g, 50%) as an off white solid; ¹H nmr (400 MHz,CDCl₃) δ 11.73 (1H, s, NH), 8.51 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.33 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3or H-5), 8.16 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5),8.05 (1H, s pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 7.65 (1H, td,J 9.0, 6.5 Hz, pyridineH-4 or H-5), 6.88 (1H, ddd, J 8.0, 3.0, 2.5 Hz,pyridineH-4 or H-5), 6.39 (1H, dq, J 7.5, 6.5 Hz, NCH(CH₃)O), 4.27 (1H,tt, J 11.5, 3.5 Hz, cyclohexaneH-1 or H-4), 3.56 (2H, q, J 7.0 Hz,OCH₂CH₃), 3.37 (1H, tt, J 10.5, 4.5 Hz, cyclohexaneH-1 or H-4),2.32-2.26 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.26-1.90 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.94 (3H, d, J 6.5 Hz, NCH(CH₃)O), 1.93-1.84 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.52-1.42(11H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6, 1×C(CH₃)₃), 1.37 (9H, s,1×C(CH₃)₃), 1.23 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, CDCl₃) δ−72.3, −124.5; ³²P nmr (162 MHz, CDCl₃) δ −11.9; m/z: 758 [M+Na]⁺. Thefiltrate contains further product.

IV. Preparation of1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyldihydrogen phosphate

A solution of the di-tert-butyl phosphate (0.202 g, 0.275 mmol) indichloromethane (3 mL) was cooled to 0° C. and phosphoric acid (85%, 9mL) was added. The reaction was stirred at room temperature for 3minutes before adding to water (60 mL). The organics were extracted withEtOAc (3×40 mL). The combined organics were dried (Na₂SO₄) andconcentrated under reduced pressure to approximately 7 mL. A precipitateformed, which was isolated by filtration to obtain the title compound(0.082 g, 48%) as a pink solid; ¹H nmr (400 MHz, D₆-DMSO) δ 11.45 (1H,s, NH), 8.55 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.50(1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.30 (1H, s,pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.13 (1H, s pyrazoleH-5,thiazoleH-5, pyrazoleH-3 or H-5), 8.06 (1H, td, J 9.5, 6.5 Hz,pyridineH-4 or H-5), 7.24 (1H, dt, J 9.0, 2.5 Hz, pyridineH-4 or H-5),6.28-6.21 (1H, m, NCH(CH₃)O), 4.31 (1H, br t, J 11.5 Hz, cyclohexaneH-1or H-4), 3.46 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.30 (1H, br t, J 10.5 Hz,cyclohexaneH-1 or H-4), 2.10-2.03 (4H, m, 4H of cyclohexaneH-2, H-3,H-5, H-6), 1.88-1.78 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.77(3H, d, J 6.0 Hz, NCH(CH ₃)O), 1.38-1.29 (2H, m, 2H of cyclohexaneH-2,H-3, H-5, H-6), 1.08 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz,D₆-DMSO) δ −72.8, −124.2; ³²P nmr (380 MHz, D₆-DMSO) δ −3.3; m/z: 624[M+H]⁺ (found [M+H]⁺, 624.1610, C₂₅H₂₈F₂N₇O₆PS requires [M+H]⁺624.1600).

To a suspension of the di-tert-butyl phosphate (0.100 g, 0.136 mmol, 1.0eq) in tetrahydrofuran (0.8 mL) water (0.8 mL, distilled, deionized,18Ω) was added sodium acetate (0.008 g, 0.010 mmol, 0.75 eq). Thereaction was sealed and stirred at 70° C. for 5.5 hours before coolingand adding acetone (20 mL). A precipitate resulted, which was isolatedby filtration to obtain the title compound (0.055 g, 65%) as a whitesolid; data agrees with that stated above.

V. Preparation of Sodium1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethylphosphate (I-20)

A suspension of the phosphate (I-18) (2.34 g, 3.75 mmol, 1.0 eq) inacetonitrile (15 mL) and water (20 mL) was cooled to 0° C. and sodiumhydroxide (0.27 g in 5 mL of water, 6.76 mmol, 1.8 eq) was addeddropwise over 30 minutes (approximately 4 mL of solution added, reactionmixture pH about 9). The reaction was stirred at 0° C. for a further 15minutes before water (10 mL) was added. The mixture was stirred for 15minutes at 0° C. and filtered (filter paper). The filtrate was frozenand dried by lyophylisation to obtain the title compound (2.40 g, 96%)as a white powder; ¹H nmr (400 MHz, D₂O) δ 8.05 (1H, s, pyrazoleH-5,thiazoleH-5, pyrazoleH-3 or H-5), 7.86 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 7.55 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3or H-5), 7.52 (1H, s pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 7.37(1H, m, pyridineH-4 or H-5), 6.59 (1H, m, pyridineH-4 or H-5), 6.00 (1H,t, J 7.5 Hz, NCH(CH₃)O), 3.94 (1H, m, cyclohexaneH-1 or H-4), 3.56 (2H,q, J 7.0 Hz, OCH ₂CH₃), 3.43 (1H, m, cyclohexaneH-1 or H-4), 2.16-2.08(2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.07-2.00 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.69 (3H, d, J 6.0 Hz, NCH(CH ₃)O),1.68-1.60 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.36-1.25 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH₂CH₃); ¹³C nmr (100 MHz, D₂O) δ 160.4, 157.9, 156.8 (d, J 237 Hz), 152.4(d, J 256.5 Hz), 147.5, 137.2 (d, J 10.5 Hz), 135.9 (t, J 14.5 Hz),132.0 (d, J 9.0 Hz), 130.2 (dd, J 25.0, 8.5 Hz), 128.0, 122.7, 120.4,119.2, 116.0, 108.6 (d, J 41.0 Hz), 82.1, 76.7, 63.8, 60.7, 30.5, 30.2,22.1, 14.5; ¹⁹F nmr (380 MHz, D₂O) δ −72.8, −124.8; ³²P nmr (162 MHz,D₂O) δ 1.2; m/z: 624 [M+H]⁺.

VI. Preparation of Sodium1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethylhydrogen phosphate (1-107)

To a suspension of the di-tert-butyl phosphate (1.81 g, 2.47 mmol, 1.0eq) in tetrahydrofuran (14.5 mL) was added sodium acetate (0.15 g, 1.85mmol, 0.75 eq). Water (14.5 mL, distilled, deionized, 18Ω) was added andthe reaction stirred at 70° C. for 8 hours. The reaction was analyzed athourly intervals from 4 hours and heating continued until the profileshowed approximately 10% of the monophosphate and 70% product (prolongedheating may result in product decomposition). The reaction was cooledand added to acetone (75 mL) resulting in a precipitate, which wasisolated by filtration to obtain the title compound (1.04 g, 67%) as awhite solid; IR ν_(max) (film) 3427, 2935, 2869, 1660, 1593, 1556, 1490,1372, 1333, 1229, 1103, 1092, 1022, 963, 823, 784, 713, 665, 647 cm⁻¹;¹H nmr (400 MHz, D₆-DMSO) δ 11.43 (1H, s, NH), 8.42 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.47 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.23 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.04 (1H, dt, J 9.5, 6.5Hz, pyridineH-4 or H-5), 8.03 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3, H-5), 7.27 (1H, dt, J 8.5, 2.5 Hz, 1H of pyridineH-4 orH-5), 6.11 (1H, dq, J 3.5, 6.0 Hz, NCH(CH₃)O), 4.31 (1H, tt, J 11.5, 3.5Hz, cyclohexaneH-1 or H-4), 3.47 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.35 (1H,tt, J 10.5, 3.5 Hz, cyclohexaneH-1 or H-4), 2.12-2.05 (4H, m, 4H ofcyclohexaneH-2, H-3, H-5, H-6), 1.90-1.80 (2H, m, 2H of cyclohexaneH-2,H-3, H-5, H-6), 1.63 (3H, d, J 6.0 Hz, CHCH ₃), 1.41-1.30 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH₂CH ₃); m/z:624 [M+H]⁺.

VII. Preparation of Potassium1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethylhydrogen phosphate

A similar procedure was used to the procedure provided above for thesodium salt but using potassium acetate instead of sodium acetate, andthe reaction may take longer to reach completion. ¹H nmr (400 MHz,D₆-DMSO) δ 11.43 (1H, s, NH), 8.47 (1H, s, 1H of pyrazoleH-5,thiazoleH-5, pyrazoleH-3, H-5), 8.46 (1H, s, 1H of pyrazoleH-5,thiazoleH-5, pyrazoleH-3, H-5), 8.22 (1H, s, 1H of pyrazoleH-5,thiazoleH-5, pyrazoleH-3, H-5), 8.07-8.00 (1H, m, pyridineH-4 or H-5),8.02 (1H, s, 1H of pyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 7.25(1H, d, J 8.5 Hz, 1H of pyridineH-4 or H-5), 6.10 (1H, dq, J 9.0, 6.0Hz, NCH(CH₃)O), 4.30 (1H, br t, J 11.5 Hz, cyclohexaneH-1 or H-4), 3.47(2H, q, J 7.0 Hz, OCH ₂CH₃), 3.34 (1H, br t, J 10.5 Hz, cyclohexaneH-1or H-4), 2.12-2.03 (4H, m, 4H of cyclohexaneH-2, H-3, H-5, H-6),2.00-1.78 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.63 (3H, d, J6.0 Hz, CHCH ₃), 1.39-1.29 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6),1.09 (3H, t, J 7.0 Hz, OCH₂CH ₃); ³²P nmr (162 MHz, D₆-DMSO) δ −2.0; ¹⁹Fnmr (380 MHz, D₆-DMSO) δ −72.5 (d, J 27.5 Hz), −124.4 (dd, J 30.5, 11.0Hz); m/z: 624 [M+H]⁺.

VIII. Preparation of 2-amino-2-(hydroxymethyl)propane-1,3-diol1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethylhydrogen phosphate (I-49)

A similar procedure was used to the procedure provided above for thesodium salt but using tris(hydroxymethyl)aminomethane. ¹H nmr (400 MHz,D₆-DMSO) δ 11.45 (1H, s, NH), 8.49 (1H, s, 1H of pyrazoleH-5,thiazoleH-5, pyrazoleH-3, H-5), 8.47 (1H, s, 1H of pyrazoleH-5,thiazoleH-5, pyrazoleH-3, H-5), 8.25 (1H, s, 1H of pyrazoleH-5,thiazoleH-5, pyrazoleH-3, H-5), 8.08-8.02 (1H, m Hz, pyridineH-4 orH-5), 8.05 (1H, s, 1H of pyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5),7.27 (1H, br d, J 8.5 Hz, 1H of pyridineH-4 or H-5), 6.11 (1H, dq, J9.0, 6.0 Hz, NCH(CH₃)O), 4.31 (1H, br t, J 11.5 Hz, cyclohexaneH-1 orH-4), 3.46 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.40 (6H, s, NH₂C(CH ₂OH)₃),3.34 (1H, br t, J 10.0 Hz, cyclohexaneH-1 or H-4), 2.12-2.04 (4H, m, 4Hof cyclohexaneH-2, H-3, H-5, H-6), 1.89-1.79 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.65 (3H, d, J 6.0 Hz, CHCH ₃),1.39-1.29 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.09 (3H, t, J7.0 Hz, OCH₂CH ₃); ³²P nmr (162 MHz, D₆-DMSO) δ −1.7; ¹⁹F nmr (380 MHz,D₆-DMSO) δ −72.5 (d, J 27.5 Hz), −124.4 (dd, J 30.5, 11.0 Hz); n/z: 624[M+H]⁺.

Example 14 Synthesis of(4-(4-((3-(3,6-Difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylIsopropyl Carbonate (I-45)

To a solution ofN-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide(50 mg, 0.1 mmol) and chloromethyl isopropyl carbonate (20 mg, 0.13mmol) in anhydrous DMF (1 mL) was added cesium carbonate (40 mg, 0.12mmol). The resulting reaction mixture was then allowed to stir atambient temperature overnight and then diluted with water (50 mL) toprovide upon filtration and drying(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylisopropyl carbonate as a white solid, wt. 49 mg (80%). ¹H NMR (400 MHz,CD₃OD) δ 11.73 (s, 1H), 8.55-8.47 (m, 2H), 8.26-8.15 (m, 2H), 7.88 (ddd,J=9.7, 8.8, 6.2 Hz, 1H), 7.14-7.06 (m, 1H), 6.11 (d, J=4.3 Hz, 2H),4.96-4.88 (m, 1H), 4.36-4.25 (m, 1H), 3.60 (qd, J=7.0, 1.4 Hz, 2H),3.52-3.42 (m, 1H), 2.31-2.18 (m, 4H), 1.97 (q, J=11.5 Hz, 2H), 1.54-1.41(m, 2H), 1.29 (d, J=6.3 Hz, 6H), 1.21 (t, J=7.0 Hz, 3H). MS m/e:Calculated 615.21; Found 616.2 (M+H)⁺.

Example 15 Synthesis of(4-(4-((3-(3,6-Difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl4-((S)-2-amino-3-methylbutanamido)butanoate Hydrochloride (I-57)

I. Synthesis of Methyl(S)-4-(2-((tert-Butoxycarbonyl)amino)-3-methylbutanamido)butanoate (3)

To a solution of methyl 4-aminobutanoate hydrogen chloride salt 1 (306mg, 2.0 mmol) and (tert-butoxycarbonyl)-L-valine 2 (433 mg, 2.0 mmol) inanhydrous DMF (5 mL) was added diisopropylethylamine (568 mg, 0.76 mL,4.4 mmol). The mixture was then cooled down to 0° C. and HATU (835 mg,2.2 mmol) was added and the resulting solution was allowed to warm up toambient temperature and stirred for 17 hours. Water (50 mL) and ethylacetate (100 mL) were then added and the organic layer was separated,washed with water (3×30 mL), brine (30 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue obtained was purified by chromatography using 0 to 100% ethylacetate in hexane gradient to afford methyl(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)butanoate 3(591 mg, 94%) as a pale sticky oil. MS m/e: Calculated 316.20; Found261.1 [M−^(t)Bu+H]⁺.

II. Synthesis of(S)-4-(2-((tert-Butoxycarbonyl)amino)-3-methylbutanamido)butanoic Acid(4)

To a solution of methyl(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)butanoate 3(583 mg, 1.85 mmol) in a mixture of THF (4 mL) and MeOH (1 mL) was addedNaOH aqueous solution (1 mL, 4N, 4 mmol). The resulting solution wasstirred at ambient temperature for 15 hours. Most of the solvent mixturewas removed under reduced pressure and water (50 mL) was added to theobtained residue. The aqueous layer was then washed with ethyl ether (50mL), acidified with aqueous HCl (5 mL, 1N) to pH 4 and extracted withethyl acetate (3×40 mL). Combined organic layer was washed with brine(20 mL), dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure to afford(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)butanoic acid 4(480 mg, 86%) as a white solid. MS m/e: Calculated 302.18; Found 247.2[M-^(t)Bu+H]⁺.

III. Synthesis of Chloromethyl(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)butanoate (6)

To a solution of(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)butanoic acid 4(370 mg, 1.23 mmol) in a mixture of dichloromethane (7 mL) and water (7mL), were added sodium bicarbonate (412 mg, 4.90 mmol) andtetrabutylammonium bisulfate (42 mg, 0.123 mmol), followed bychloromethyl chlorosulfate 5 (233 mg, 143 μL, 1.41 mmol). The resultingsolution was stirred at ambient temperature for 2 days anddichloromethane (80 mL) and water (30 mL) were added. The organic layerwas separated, and the aqueous layer was extracted with dichloromethane(30 mL). The combined organic layers were dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure to affordcrude product which was further purified by chromatography using 0 to100% ethyl acetate in hexane gradient to afford chloromethyl(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)butanoate 6(369 mg, 86%) as a colorless oil. MS m/e: Calculated 350.16; Found 251.1[M−Boc+H]⁺.

IV. Synthesis of(4-(4-((3-(3,6-Difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl4-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)butanoate (8)

To a solution of chloromethyl(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido) butanoate 6(45 mg, 0.128 mmol) in anhydrous DMF (1 mL) was addeddiisopropylethylamine (33.2 mg, 45 μL, 0.128 mmol) followed byN-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide7 (64 mg, 0.128 mmol). The resulting solution was stirred at ambienttemperature for 2 days, then water (20 mL) was added and the aqueoussolution was extracted with ethyl acetate (2×40 mL). The combinedorganic layers were then washed with brine (20 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresulting crude product was purified by reverse phase HPLC (40 to 100%acetonitrile in water buffered with 0.1% formic acid). Desired fractionswere combined and lyophilized to afford(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl4-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)butanoate 8 (26mg, 25%) as a white foam. MS m/e: Calculated 813.34; Found 814.3 [M+H]⁺.

V. Synthesis of(4-(4-((3-(3,6-Difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl4-((S)-2-amino-3-methylbutanamido)butanoate Hydrochloride (I-57)

To a suspension of(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl4-((S)-2-((tert-butoxycarbonyl) amino)-3-methylbutanamido)butanoate 8(26 mg, 0.032 mmol) in ethyl acetate was added HCl (0.31 mL, 4M indioxane). The resulting solution was stirred at ambient temperature for19 hours. A cloudy solution was obtained, filtered and the resultingsolid was washed with ethyl acetate and hexanes and dried under highvacuum to afford(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl4-((S)-2-amino-3-methylbutanamido)butanoate hydrogen chloride (21.4 mg,89%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.51-8.48 (m, 2H), 8.22(d, J=0.7 Hz, 1H), 8.20 (s, 1H), 7.89 (td, J=9.2, 6.2 Hz, 1H), 7.09(ddd, J=8.8, 3.4, 2.6 Hz, 1H), 6.15 (s, 2H), 4.31 (ddd, J=11.7, 8.4, 3.7Hz, 1H), 3.61 (q, J=7.0 Hz, 2H), 3.53 (d, J=5.9 Hz, 1H), 3.50-3.40 (m,1H), 3.27 (dt, J=6.9, 3.4 Hz, 2H), 2.48 (t, J=7.4 Hz, 2H), 2.30-2.17 (m,4H), 2.11 (dq, J=13.4, 6.4 Hz, 1H), 2.05-1.91 (m, 2H), 1.86 (p, J=7.2Hz, 2H), 1.47 (q, J=11.8 Hz, 2H), 1.21 (t, J=7.0 Hz, 3H), 1.01 (dd,J=6.9, 5.4 Hz, 6H). MS m/e: Calculated 713.29; Found 714.3 [M+H]⁺.

Example 16 Synthesis of(4-(4-((3-(3,6-Difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl1-Amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate Hydrochloride (I-61)

I. Synthesis of Chloromethyl2,2-Dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oate(11)

To a solution of2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oicacid (250 mg, 0.551 mmol) 10 in the mixture of dichloromethane (5.2 mL)and water (5.2 mL) were added sodium bicarbonate (185 mg, 2.21 mmol) andtetrabutylammonium bisulfate (18.7 mg, 0.0551 mmol). Chloromethylchlorosulfate 5 (105 mg, 64 μL, 0.634 mmol) was then added and theresulting solution was stirred at ambient temperature for 18 hours.Water (10 mL) was then added, and the resulting aqueous solution wasextracted with dichloromethane (3×30 mL). The combined organic layerswere washed with brine (20 mL), dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to afford crude productof chloromethyl2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oate 11(303 mg, 100%) with 91% purity. The crude product was directly used innext step without further purification. MS m/e: Calculated 501.23; Found402.1 [M−Boc+H]⁺.

II. Synthesis of(4-(4-((3-(3,6-Difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oate(12)

To a solution of chloromethyl2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oate 11(51.8 mg, 0.103 mmol) andN-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide7 (51.5 mg, 0.103 mmol) in anhydrous DMF (1 mL) was added anhydrouscesium carbonate (37 mg, 0.113 mmol). The resulting reaction mixture wasstirred at ambient temperature for 16 hours. Water (20 mL) and ethylacetate (100 mL) were then added, and the organic layer was separated,washed with brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The residue obtained was purifiedby reverse phase HPLC (30 to 100% acetonitrile in water buffered with0.1% formic acid). The desired fractions were combined, lyophilized toafford(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oate 12(57.4 mg, 58%) as a colorless sticky oil. MS m/e: Calculated 964.42;Found 865.3[M−Boc+H]⁺.

III. Synthesis of(4-(4-((3-(3,6-Difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl1-Amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate Hydrochloride (I-61)

To a solution of(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oate 12(57.4 mg, 0.0595 mmol) in ethyl acetate (5 mL) was added HCl (2.4 mL, 1Min ethyl ether, 2.4 mmol). The resulting solution was stirred at ambienttemperature for 2 days. All solvents were removed under reduced pressureand the residue obtained was purified by reverse phase HPLC (0 to 70%acetonitrile in water buffered with 0.1% formic acid). The desiredfractions were combined and HCl solution (65 μL, 1N) was added andlyophilized to afford(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate hydrochloride (19 mg,35%) as a sticky pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 11.71 (s,1H), 8.50 (s, 2H), 8.28-8.16 (m, 2H), 7.90 (td, J=9.2, 6.1 Hz, 1H),7.21-7.00 (m, 1H), 6.17 (s, 2H), 4.31 (ddd, J=11.8, 8.3, 3.7 Hz, 1H),3.76 (t, J=5.9 Hz, 2H), 3.72-3.48 (m, 24H), 3.06 (t, J=5.1 Hz, 2H), 2.70(t, J=5.9 Hz, 2H), 2.66 (s, 1H), 2.30-2.17 (m, 4H), 1.97 (dt, J=13.7,11.2 Hz, 2H), 1.56-1.41 (m, 2H), 1.29 (s, 3H), 1.21 (t, J=7.0 Hz, 3H).MS m/e: Calculated 864.37; Found 865.3 [M+H]⁺.

Example 17 Synthesis of Isopropyl(((4-(4-((3-(3,6-Difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate(I-62)

I. Synthesis ofN-(3-(3,6-Difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(hydroxymethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide(14)

To a solution ofN-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide7 (501 mg, 1 mmol) in absolute ethanol (3 mL) was added formaldehydeaqueous solution (162 mg, 0.15 mL, 37% wt., 2 mmol). The resultingsolution was heated at 50° C. for 18 hours, and the resulting cloudyreaction mixture was filtered, washed with absolute ethanol and hexanes.The white solid obtained was placed under high vacuum to affordN-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(hydroxymethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide14 (385 mg, 73%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.47 (s, 1H), 8.52 (d,J=8.5 Hz, 2H), 8.31 (s, 1H), 8.10 (d, J=15.2 Hz, 2H), 7.28 (s, 1H), 6.99(s, 1H), 5.43 (d, J=7.7 Hz, 2H), 4.33 (s, 1H), 3.47 (d, J=7.4 Hz, 2H),2.08 (d, J=11.9 Hz, 4H), 1.86 (d, J=13.4 Hz, 2H), 1.35 (d, J=12.3 Hz,2H), 1.10 (t, J=7.0 Hz, 3H). MS m/e: Calculated 529.17; Found 530.1[M+H]⁺.

II. Synthesis of Isopropyl(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate(I-62)

To a solution ofN-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(hydroxymethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide14 (57.3 mg, 0.108 mmol) in anhydrous dichloromethane (2 mL),diisopropylethylamine (28 mg, 38 μL, 0.217 mmol) was added followed byisopropyl (chloro(phenoxy)phosphoryl)-L-alaninate 15 (36.4 mg, 30 μL,0.119 mmol). The resulting solution was stirred at ambient temperaturefor 2 days and then concentrated under reduced pressure. The residueobtained was purified by reverse phase HPLC (50 to 100% acetonitrile inwater buffered with 0.1% formic acid) and the desired fractions werecombined and lyophilized to afford isopropyl(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate(16 mg, 19%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.51 (s, 1H),8.48 (d, J=14.4 Hz, 1H), 8.24 (d, J=4.5 Hz, 1H), 8.22 (s, 1H), 7.87(ddd, J=9.7, 8.8, 6.2 Hz, 1H), 7.33-7.25 (m, 2H), 7.21-7.01 (m, 4H),6.11 (d, J=11.8 Hz, 1H), 6.06 (dd, J=11.6, 2.3 Hz, 1H), 4.95 (pd, J=6.3,5.3 Hz, 1H), 4.38-4.25 (m, 1H), 3.99-3.81 (m, 1H), 3.60 (q, J=7.0 Hz,2H), 3.51-3.39 (m, 1H), 2.32-2.14 (m, 4H), 1.98 (q, J=12.1, 11.6 Hz,2H), 1.47 (q, J=12.1 Hz, 2H), 1.32 (ddd, J=8.8, 7.2, 1.2 Hz, 3H),1.26-1.09 (m, 9H). MS m/e: Calculated 798.25; Found 799.2 [M+H]⁺.

Example 18 Synthesis of((((4-(4-((3-(3,6-Difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(hydroxy)phosphoryl)oxy)methylisopropyl carbonate (I-60)

To a solution of(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate (1.00 g, 1.64 mmol, 1.0 eq) in dimethyl sulfoxide(10 mL) was added chloromethyl isopropyl carbonate (2.17 mL, 16.4 mmol,10 eq) and diisopropylethylamine (2.71 mL, 16.4 mmol, 10 eq). Thesolution was stirred at room temperature for 2 days. The reactionmixture was purified by reverse phase HPLC (C-18, water/acetonitrilewith 0.1% formic acid) to give the title compound (309 mg, 26%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 11.6 (s, 1H), 8.37 (s, 1H), 8.25(s, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.57-7.51 (m, 1H), 6.81-6.79 (m,1H), 5.97 (d, J=10.8 Hz, 2H), 5.65 (d, J=10.8 Hz, 2H), 4.93-4.87 (m,1H), 4.27-4.21 (m, 1H), 3.57 (q, J=7.2, 6.8 Hz, 2H), 3.41-3.35 (m, 1H),2.32-2.22 (m, 4H), 1.93-1.84 (m, 2H), 1.52-1.43 (m, 2H), 1.33-1.24 (m,9H). MS m/e: Calculated 725.18; Found 726.2 (M+H)⁺.

The following exemplary compounds were prepared using the methods ofExamples 4-18. Characterization data for these additional compounds areprovided below.

I-6:2-(1-(acetyl-L-leucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.78 (1H, s, pyrazoleH-3 or H-5), 8.50 (1H, s,thiazoleH-5 or pyrazoleH-5), 8.36 (1H, s, pyrazoleH-3 or H-5), 8.14 (1H,s, thiazoleH-5 or pyrazoleH-5), 7.65 (1H, td, J 9.0, 6.0 Hz, pyridineH-4or H-5), 6.91 (1H, ddd, J 9.0, 3.5, 2.5 Hz, pyridineH-4 or H-5), 6.11(1H, d, J 9.0 Hz, NHCOCH₃), 5.88 (1H, m, COCHNHCO), 4.27 (1H, tt, J11.5, 4.0 Hz, cyclohexaneH-1 or H-4), 3.56 (2H, q, J 7.0 Hz, OCH ₂CH₃),3.37 (1H, tt, J 10.5, 4.0 Hz, cyclohexaneH-1 or H-4), 2.30 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 2.22 (2H, m, 2H of cyclohexaneH-2, H-3,H-5, H-6), 2.08 (3H, s, COCH₃), 1.89 (2H, m, 2H of cyclohexaneH-2, H-3,H-5, H-6), 1.86-1.76 (2H, m, 2H of CHCH ₂CH(CH₃)₂), 1.65 (1H, m, 1H ofCHCH ₂CH(CH₃)₂), 1.33 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.22(3H, t, J 7.0 Hz, OCH₂CH ₃), 1.07 (3H, d, J 6.0 Hz, 1×CH₃ of CH(CH₃)₂),0.97 (3H, d, J 6.5 Hz, 1×CH₃ of CH(CH₃)₂); m/z: 677 [M+Na]⁺, 655 [M+H]⁺(found [M+H]⁺, 655.2623, C₃₁H₃₆F₂N₈O₄S requires [M+H]⁺ 655.2621).

I-7: 1-methylcyclopropyl4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate

¹H nmr (400 MHz, CDCl₃) δ 8.73 (1H, s, 1H of thiazoleH-5, pyrazoleH-5 orpyrazoleH-3, H-5), 8.50 (1H, s, 1H of thiazoleH-5, pyrazoleH-5 orpyrazoleH-3, H-5), 8.33 (1H, s, 1H of thiazoleH-5, pyrazoleH-5 orpyrazoleH-3, H-5), 8.13 (1H, s, 1H of thiazoleH-5, pyrazoleH-5 orpyrazoleH-3, H-5), 7.66 (1H, td, J 9.0, 6.0 Hz, pyridineH-4 or H-5),6.88 (1H, ddd, J 9.0, 3.5, 2.5 Hz, pyridineH-4 or H-5), 4.28 (1H, tt, J11.5, 4.0 Hz, cyclohexaneH-1 or H-4), 3.56 (2H, q, J 7.0 Hz, OCH ₂CH₃),3.37 (1H, tt, J 10.5, 4.0 Hz, cyclohexaneH-1 or H-4), 2.30 (2H, br t, J11.5 Hz, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.22 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.89 (2H, m, 2H of cyclohexaneH-2, H-3,H-5, H-6), 1.76 (3H, s, CH₃), 1.47 (2H, m, 2H of cyclohexaneH-2, H-3,H-5, H-6), 1.24 (2H, m, 2H of cPrH-2, H-3), 1.23 (3H, t, J 7.0 Hz,OCH₂CH ₃), 0.86 (2H, m, 2H of cPrH-2, H-3); ¹⁹F nmr (380 MHz, CDCl₃) δ−72.6, −124.3; m/z: 598 [M+H]⁺ (found [M+H]⁺, 598.2035, C₂₈H₂₉F₂N₇O₄Srequires [M+H]⁺ 598.2043).

I-8: 1-(isobutyryloxy)ethyl4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate

¹H nmr (400 MHz, CDCl₃) δ 8.76 (1H, s, 1H of thiazoleH-5, pyrazoleH-5,pyrazoleH-3, H-5), 8.51 (1H, s, 1H of thiazoleH-5, pyrazoleH-5,pyrazoleH-3, H-5), 8.38 (1H, s, 1H of thiazoleH-5, pyrazoleH-5,pyrazoleH-3, H-5), 8.14 (1H, s, 1H of thiazoleH-5, pyrazoleH-5,pyrazoleH-3, H-5), 7.66 (1H, td, J 9.0, 6.0 Hz, pyridineH-4 or H-5),7.15 (1H, q, J 5.5 Hz, OCH(CH₃)O), 6.87 (1H, ddd, J 9.0, 3.5, 2.5 Hz,pyridineH-4 or H-5), 4.28 (1H, tt, J 11.5, 4.0 Hz, cyclohexaneH-1 orH-4), 3.57 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.37 (1H, tt, J 10.5, 4.0 Hz,cyclohexaneH-1 or H-4), 2.63 (1H, heptet, J 7.0 Hz, COCH(CH₃)₂), 2.30(2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.22 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.90 (2H, m, 2H of cyclohexaneH-2, H-3,H-5, H-6), 1.74 (3H, d, J 5.5 Hz, OCH(CH ₃)O), 1.47 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.23 (3H, t, J 7.0 Hz, OCH₂CH ₃), 1.21(3H, d, J 7.0 Hz, 1×CH₃ of (CH(CH₃)₂), 1.21 (3H, d, J 6.5 Hz, 1×CH₃ ofCH(CH₃)₂); ¹⁹F nmr (380 MHz, CDCl₃) δ −72.6 (ddd, J 27.0, 5.5, 4.0 Hz),−124.3 (ddd, 27.0, 9.5, 2.5 Hz); m/z: 658 [M+H]⁺ (found [M+H]⁺,658.2553, C₃₀H₃₃F₂N₇O₆S requires [M+H]⁺658.2254).

I-9:N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.50 (1H, s, 1H of thiazoleH-5, pyrazoleH-5,pyrazoleH-3, H-5), 8.49 (1H, s, 1H of thiazoleH-5, pyrazoleH-5,pyrazoleH-3, H-5), 8.11 (1H, s, 1H of thiazoleH-5, pyrazoleH-5,pyrazoleH-3, H-5), 8.09 (1H, s, 1H of thiazoleH-5, pyrazoleH-5,pyrazoleH-3, H-5), 7.67 (1H, td, J 9.0, 6.5 Hz, pyridineH-4 or H-5),6.92 (1H, dt, J 9.0, 3.0 Hz, pyridineH-4 or H-5), 5.19 (1H, d, J 4.5 Hz,1H of NCH₂C), 4.73 (1H, d, J 4.5 Hz, 1H of NCH₂C), 4.28 (1H, tt, J 11.5,4.0 Hz, cyclohexaneH-1 or H-4), 3.57 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.38(1H, tt, J 10.5, 4.0 Hz, cyclohexaneH-1 or H-4), 2.36 (3H, s, CCH₃),2.30 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.23 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.90 (2H, m, 2H of cyclohexaneH-2, H-3,H-5, H-6), 1.48 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.23 (3H,t, J 7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, CDCl₃) δ −73.5, −124.1 (ddd,27.0, 9.5, 3.0 Hz); m/z: 612 [M+H]⁺ (found [M+H]⁺, 612.1835,C₂₈H₂₇F₂N₇O₅S requires [M+H]⁺ 612.1857).

I-10: 2-morpholinoethyl4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate

¹H nmr (400 MHz, CDCl₃) δ 8.75 (1H, s, 1H of thiazoleH-5, pyrazoleH-5,pyrazoleH-3, H-5), 8.49 (1H, s, 1H of thiazoleH-5, pyrazoleH-5,pyrazoleH-3, H-5), 8.35 (1H, s, 1H of thiazoleH-5, pyrazoleH-5,pyrazoleH-3, H-5), 8.13 (1H, s, 1H of thiazoleH-5, pyrazoleH-5,pyrazoleH-3, H-5), 7.64 (1H, td, J 9.0, 6.0 Hz, pyridineH-4 or H-5),6.86 (1H, dt, J 8.5, 3.5, 2.5 Hz, pyridineH-4 or H-5), 4.63 (2H, t, J6.0 Hz, COOCH ₂CH₂N), 4.26 (1H, tt, J 11.5, 4.0 Hz, cyclohexaneH-1 orH-4), 3.70, 3.68 (4H, 2d AB system, J 4.5 Hz, 4H of morpholine), 3.55(2H, q, J 7.0 Hz, OCH ₂CH₃), 3.36 (1H, tt, J 10.5, 4.0 Hz,cyclohexaneH-1 or H-4), 2.84 (2H, t, J 6.0 Hz, COOCH2CH2N), 2.58, 2.57(4H, 2d AB system, J 4.5 Hz, 4H of morpholine), 2.28 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 2.20 (2H, m, 2H of cyclohexaneH-2, H-3,H-5, H-6), 1.88 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.45 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.21 (3H, t, J 7.0 Hz, OCH₂CH₃); ¹⁹F nmr (380 MHz, CDCl₃) δ −72.7 (ddd, J 27.0, 5.5, 4.0 Hz), −124.3(ddd, 27.0, 11.0, 9.5 Hz); m/z: 657 [M+H]⁺.

I-12:N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(morpholine-4-carbonyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.71 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.50 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3or H-5), 8.26 (1H, d, J 0.5 Hz), 8.10 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 7.64 (1H, td, J 9.0, 6.0 Hz, pyridineH-4 or H-5),6.90 (1H, ddd, J 9.0, 3.5, 2.5 Hz, pyridineH-4 or H-5), 4.27 (1H, tt, J11.5, 4.0 3.83, 3.82 (4H, 2d AB system, J 4.0 Hz, 4H of morpholine),3.56 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.36 (1H, tt, J 11.0, 4.0 Hz,cyclohexaneH-1 or H-4), Hz, cyclohexaneH-1 or H-4), 3.94 (4H, br s, 4Hof morpholine), 2.33-2.25 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6),2.55-1.90 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.94-1.84 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.52-1.41 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.22 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹Fnmr (380 MHz, CDCl₃) δ −72.5, −124.4; m/z: 613 [M+H]⁺ (found [M+H]⁺,613.2163, C₂₈H₃₀F₂N₈O₄S requires [M+H]⁺ 613.2152).

I-13:N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((3-morpholinopropyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.85 (1H, t, J 5.0 Hz, CONHCH₂), 8.79 (1H, s,pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.49 (1H, s, pyrazoleH-5,thiazoleH-5, pyrazoleH-3 or H-5), 8.25 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.08 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3or H-5), 7.36 (1H, td, J 9.0, 6.0 Hz, pyridineH-4 or H-5), 6.90 (1H,ddd, J 9.0, 3.5, 2.5 Hz, pyridineH-4 or H-5), 4.26 (1H, tt, J 12.0, 4.0Hz, cyclohexaneH-1 or H-4), 3.85, 3.84 (4H, 2d AB system, J 4.5 Hz, 4Hof morpholine), 3.60-3.56 (2H, m, CONHCH ₂CH₂CH₂N), 3.55 (2H, q, J 7.0Hz, OCH ₂CH₃), 3.36 (1H, tt, J 10.5, 4.0 Hz, cyclohexaneH-1 or H-4),2.57-2.54 (2H, m, CONHCH₂CH₂CH ₂N), 2.51 (4H, br s, 4H of morpholine),2.30-2.26 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.23-2.18 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.93-1.84 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.84-1.78 (2H, m, CONHCH₂CH ₂CH₂N),1.51-1.41 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.21 (3H, t, J7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, CDCl₃) δ −72.6 (ddd, J 27.0, 5.5,4.0 Hz), −124.5 (ddd, J 27.0, 9.5, 2.5 Hz); m/z: 670 [M+H]⁺.

I-14:N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((3-(dimethylamino)propyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H nmr (400 MHz, CDCl₃) δ 8.80 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.49 (1H, s pyrazoleH-5, thiazoleH-5, pyrazoleH-3or H-5), 8.36 (1H, t, J 5.5 Hz, pyrazoleCONH), 8.20 (1H, d, J 0.5 Hz,pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.08 (1H, s, pyrazoleH-5,thiazoleH-5, pyrazoleH-3 or H-5), 7.63 (1H, td, J 9.0, 6.0 Hz,pyridineH-4 or H-5), 6.89 (1H, ddd, J 9.0, 3.5, 2.5 Hz, pyridineH-4 orH-5), 4.26 (1H, tt, J 11.5, 4.0 Hz, cyclohexaneH-1 or H-4), 3.58-3.52(4H, m, OCH ₂CH₃, pyrazoleCONHCH ₂), 3.36 (1H, tt, J 10.5, 4.0 Hz,cyclohexaneH-1 or H-4), 2.44 (2H, t, J 6.5 Hz, CH ₂N(CH₃)₂), 2.26 (6H,s, N(CH₃)₂), 2.30-2.18 (4H, m, 4H of cyclohexaneH-2, H-3, H-5, H-6),1.93-1.83 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.79 (2H,pentet, J 6.5 Hz, NCH₂CH ₂CH₂N(CH₃)₂), 1.51-1.41 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.21 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹Fnmr (380 MHz, CDCl₃) δ −72.6, −124.5; m/z: 628 [M+H]⁺ (found [M+H]⁺,628.2628, C₂₉H₃₅F₂N₉O₃S requires [M+H]⁺ 628.2624).

I-15: 3-morpholinopropyl4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate

¹H nmr (400 MHz, CDCl₃) δ 8.75 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.49 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3or H-5), 8.34 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5),8.12 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 7.64 (1H,td, J 9.0, 6.0 Hz, pyridineH-4 or H-5), 6.87 (1H, ddd, J 9.0, 3.5, 2.5Hz, pyridineH-4 or H-5), 4.61 (2H, 6.5 Hz, 2H of OCH ₂CH ₂CH₂N), 4.26(1H, tt, J 11.5, 4.0 Hz, cyclohexaneH-1 or H-4), 3.66, 3.65 (4H, 2d ABsystem, J 4.5 Hz, 4H of morpholine), 3.55 (2H, q, J 7.0 Hz, OCH ₂CH ₃),3.35 (1H, tt, J 10.5, 4.0 Hz, cyclohexaneH-1 or H-4), 2.52 (2H, J 7.0Hz, 2H of OCH₂CH ₂CH₂N), 2.44 (4H, m, 4H of morpholine), 2.30-2.24 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.24-2.17 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 2.05 (2H, pentet, J 6.5 Hz, OCH₂CH₂CH₂N), 1.93-1.83 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6),1.51-1.41 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.21 (3H, t, J7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, CDCl₃) δ −72.7 (ddd, J 28.5, 5.5,4.0 Hz), −124.3 (ddd, J 28.0, 9.5, 2.5 Hz); m/z: 671 [M+H]⁺ (found[M+H]⁺, 671.2560, C₃₁H₃₆F₂N₈O₅S requires [M+H]⁺ 671.2570).

I-16:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylL-valinate hydrogen chloride salt

¹H nmr (400 MHz, D₆-DMSO) δ 8.66 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.51 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3or H-5), 8.35 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5),8.22 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.07 (1H,td, J 9.0, 6.0 Hz, pyridineH-4 or H-5), 7.25 (1H, ddd, J 8.5, 3.0, 2.5Hz, pyridineH-4 or H-5), 6.2×, 6.2× (2d, AB system, J Hz, NCH₂OCO), 4.32(1H, tt, J 11.5, 3.0 Hz, cyclohexaneH-1 or H-4), 3.90 (1H, d, J 4.0 Hz,COCHNH₂), 3.45 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.30 (1H, tt, J 11.0, 4.0Hz, cyclohexaneH-1 or H-4), 2.12-2.00 (5H, m, 4H of cyclohexaneH-2, H-3,H-5, H-6, CH(CH₃)₂), 1.88-1.80 (2H, m, 2H of cyclohexaneH-2, H-3, H-5,H-6), 1.38-1.29 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.08 (3H,t, J 7.0 Hz, OCH₂CH ₃), 0.87 (3H, d, J 7.0 Hz, 3H of CH(CH ₃)₂), 0.83(3H, d, J 7.0 Hz, 3H of CH(CH ₃)₂); ¹³C nmr (100 MHz, D₆-DMSO) δ 168.8,160.2, 157.6, 157.5 (d, J 236.0 Hz), 153.5 (dd, J 259.0, 4.5 Hz), 149.4,139.5 (d, 6.5 Hz), 138.2 (t, J 14.5 Hz), 132.6 (d, 8.5 Hz), 132.3, 131.9(dd, 22.5, 9.5 Hz), 124.4, 121.4, 120.3, 117.8, 109.2 (br d, J 34.0 Hz),76.0, 73.6, 63.0, 60.8, 57.4, 30.9 (2C), 29.8, 18.6, 17.7, 16.1; ¹⁹F nmr(380 MHz, D₆-DMSO) δ −73.0 (d, J 28.5 Hz), −124.1 (dd, J 27.0, 9.5 Hz);m/z: 629 [M+H]⁺ (found [M+H]⁺, 629.2477, C₂₉H₃₄F₂N₈O₄S requires [M+H]⁺629.2465).

I-17:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylL-prolinate hydrogen chloride salt

¹H nmr (400 MHz, D₆-DMSO) δ 11.48 (1H, s, 1×NH), 9.32 (1H, br s, 1×NH),8.66 (1H, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.51 (1H, s,pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.35 (1H, s, pyrazoleH-5,thiazoleH-5, pyrazoleH-3 or H-5), 8.22 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.07 (1H, td, J 9.5, 6.5 Hz, pyridineH-4 or H-5),7.26 (1H, dt, J 8.5, 2.5 Hz, pyridineH-4 or H-5), 6.24 (2H, s, NCH₂OCOCHN), 4,42 (1H, tt, J 8.5, 3.5 Hz, cyclohexaneH-1 or H-4), 3.45 (2H,q, J 7.0 Hz, OCH ₂CH₃), 3.33 (1H, tt, J 10.0, 4.0 Hz, cyclohexaneH-1 orH-4), 3.23-3.11 (2H, m, COCHNHCH ₂), 2.27-2.19 (1H, m, 1H of COCH(NH)CH₂), 2.10-2.04 (4H, m, 4H of cyclohexaneH-2, H-3, H-5, H-6), 1.98-1.80(5H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6, 3H of COCH(NH)CH ₂CH ₂),1.38-1.29 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.08 (3H, t, J7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, D₆-DMSO) δ −73.0 (d, J 27.5 Hz),−124.1 (dd, J 27.0, 9.5 Hz); m/z: 627 [M+H]⁺.

I-18:1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyldihydrogen phosphate

¹H nmr (400 MHz, D₆-DMSO) δ 11.45 (1H, s, NH), 8.55 (1H, s, pyrazoleH-5,thiazoleH-5, pyrazoleH-3 or H-5), 8.50 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.30 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3or H-5), 8.13 (1H, s pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.06(1H, td, J 9.5, 6.5 Hz, pyridineH-4 or H-5), 7.24 (1H, dt, J 9.0, 2.5Hz, pyridineH-4 or H-5), 6.28-6.21 (1H, m, NCH(CH₃)O), 4.31 (1H, br t, J11.5 Hz, cyclohexaneH-1 or H-4), 3.46 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.30(1H, br t, J 10.5 Hz, cyclohexaneH-1 or H-4), 2.10-2.03 (4H, m, 4H ofcyclohexaneH-2, H-3, H-5, H-6), 1.88-1.78 (2H, m, 2H of cyclohexaneH-2,H-3, H-5, H-6), 1.77 (3H, d, J 6.0 Hz, NCH(CH ₃)O), 1.38-1.29 (2H, m, 2Hof cyclohexaneH-2, H-3, H-5, H-6), 1.08 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹Fnmr (380 MHz, D₆-DMSO) δ −72.8, −124.2; ³²P nmr (380 MHz, D₆-DMSO) δ−3.3; m/z: 624 [M+H]⁺ (found [M+H]⁺, 624.1610, C₂₅H₂₈F₂N₇O₆PS requires[M+H]⁺ 624.1600).

I-19:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylglycinate hydrogen chloride salt

¹H nmr (400 MHz, D₆-DMSO) δ 11.47 (1H, s, NH), 8.67 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.52 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.37 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.34 (2H, br s, NH₂),8.23 (1H, s, 1H of pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.09(1H, td, J 9.5, 6.5 Hz, pyridineH-4 or H-5), 7.27 (1H, dt, J 8.5, 2.5Hz, pyridineH-4 or H-5), 6.25 (2H, s, NCH₂O or COCH ₂NH₂), 4.33 (1H, tt,J 11.5, 3.5 Hz, cyclohexaneH-1 or H-4), 3.89 (2H, s, NCH₂O or COCH₂NH₂), 3.47 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.34 (1H, tt, J 11.0, 3.5 Hz,cyclohexaneH-1 or H-4), 2.12-2.04 (4H, m, 4H of cyclohexaneH-2, H-3,H-5, H-6), 1.91-1.80 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6),1.41-1.29 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H, t, J7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, D₆-DMSO) δ −72.9, −124.1; m/z: 587[M+H]⁺ (found [M+H]⁺, 587.1996, C₂₆H₂₈F₂N₈O₄S requires [M+H]⁺ 587.1995).

I-20: Sodium1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethylphosphate

¹H nmr (400 MHz, D₂O) δ 8.05 (1H, s, pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 7.86 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3or H-5), 7.55 (1H, s, pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5),7.52 (1H, s pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 7.37 (1H, m,pyridineH-4 or H-5), 6.59 (1H, m, pyridineH-4 or H-5), 6.00 (1H, t, J7.5 Hz, NCH(CH₃)O), 3.94 (1H, m, cyclohexaneH-1 or H-4), 3.56 (2H, q, J7.0 Hz, OCH ₂CH₃), 3.43 (1H, m, cyclohexaneH-1 or H-4), 2.16-2.08 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.07-2.00 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.69 (3H, d, J 6.0 Hz, NCH(CH ₃)O),1.68-1.60 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.36-1.25 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH₂CH₃); ¹⁹F nmr (380 MHz, D₂O) δ −72.8, −124.8; ³²P nmr (380 MHz, D₂O) δ1.2; m/z: 624 [M+H]⁺.

I-21:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate hydrogen chloride salt

¹H nmr (400 MHz, D₆-DMSO) δ 11.47 (1H, s, NH), 8.68 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.52 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.43 (2H, br s, NH₂),8.37 (1H, s, 1H of pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.24(1H, s, 1H of pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.09 (1H,td, J 9.5, 6.5 Hz, pyridineH-4 or H-5), 7.26 (1H, br d, J 8.5 Hz,pyridineH-4 or H-5), 6.34, 6.24 (2H, 2d AB system, J 11.0 Hz, NCH ₂O),4.33 (1H, br t, J 11.5, Hz, cyclohexaneH-1 or H-4), 3.86 (1H, s,COCH(tBu)NH₂), 3.47 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.38-3.30 (1H, m,cyclohexaneH-1 or H-4), 2.12-2.05 (4H, m, 4H of cyclohexaneH-2, H-3,H-5, H-6), 1.91-1.81 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6),1.40-1.30 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H, t, J7.0 Hz, OCH₂CH₃), 0.93 (9H, s, C(CH ₃)₃); ¹⁹F nmr (380 MHz, D₆-DMSO) δ−72.9, −124.1; m/z: 643 [M+H]⁺ (found [M+H]⁺, 643.2607, C₃₀H₃₆F₂N₈O₄Srequires [M+H]⁺ 643.2621).

I-23:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl2-amino-2-methylpropanoate hydrogen chloride salt

¹H nmr (400 MHz, D₆-DMSO) δ 8.68 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.52 (2H, br s, 2×NH), 8.52 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.37 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.24 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.09 (1H, td, J 9.0, 6.5Hz, pyridineH-4 or H-5), 7.26 (1H, dt, J 9.0, 3.0 Hz, pyridineH-4 orH-5), 6.26 (2H, s, NCH₂O), 4.33 (1H, br t, J 12.0 Hz, cyclohexaneH-1 orH-4), 3.47 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.34 (1H, tt, J 10.5, 3.5 Hz,cyclohexaneH-1 or H-4), 2.11-2.04 (4H, m, 4H of cyclohexaneH-2, H-3,H-5, H-6), 1.91-1.80 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.43(6H, s, C(CH₃)₂), 1.41-1.30 (2H, m, 2H of cyclohexaneH-2, H-3, H-5,H-6), 1.10 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, D₆-DMSO) δ−72.9, −124.1; m/z: 615 [M+H]⁺ (found [M+H]⁺, 615.2343, C₂₈H₃₂F₂N₈O₄Srequires [M+H]⁺ 615.2309).

I-24:4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoicacid

¹H nmr (400 MHz, CDCl₃) δ 11.71 (1H, s, NH), 8.48 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.29 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.14 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.06 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 7.63 (1H, td, J 9.0, 6.5Hz, pyridineH-4 or H-5), 6.88 (1H, ddd, J 8.5, 3.5, 2.5 Hz, pyridineH-4or H-5), 6.11 (2H, s, OCH₂O), 4.26 (1H, tt, J 11.5, 4.0 Hz,cyclohexaneH-1 or H-4), 3.56 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.37 (1H, tt,J 10.5, 4.0 Hz, cyclohexaneH-1 or H-4), 2.69 (4H, br s, COCH₂CH₂CO),2.32-2.2.18 (4H, m, 4H of cyclohexaneH-2, H-3, H-5, H-6), 1.94-1.83 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.52-1.42 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.22 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹³Cnmr (100 MHz, CDCl₃) δ 175.8, 171.6, 159.8, 158.2, 157.5 (d, J 237.5Hz), 153.4 (dd, J 260.5, 4.5 Hz), 150.1, 139.7 (d, J 5.0 Hz), 138.7 (t,J 14.5 Hz), 133.0 (d, J 8.5 Hz), 130.4 (d, J 5.0 Hz), 129.9 (dd, J 22.5,9.0 Hz), 122.0, 121.8, 119.4, 118.6, 107.6 (dd, J 40.5, 5.5 Hz), 76.4,72.4, 63.7, 61.5, 31.0, 30.9, 28.7, 28.5, 15.7; ¹⁹F nmr (380 MHz, CDCl₃)δ −72.5 dd, J 27.5, 9.5 Hz), −124.4 (ddd, J 28.5, 9.5, 2.5 Hz); m/z: 630[M+H]⁺ (found [M+H]⁺, 630.1927, C₂₈H₂₉F₂N₇O₆S requires [M+H]⁺630.1941).

I-28:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl2-morpholinoacetate

¹H nmr (400 MHz, CDCl₃) δ 8.50 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.31 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.17 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.06 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 7.65 (1H, td, J 9.0, 6.0 Hz, pyridineH-4 or H-5),6.89 (1H, ddd, J 8.5, 3.0, 2.5 Hz, pyridineH-4 or H-5), 6.13 (2H, s,NCH₂O), 4.27 (1H, tt, J 11.5, 3.5 Hz, cyclohexaneH-1 or H-4), 3.73, 3.72(4H, 2d AB system, J 4.5 Hz, 4H of morpholine), 3.56 (2H, q, J 7.0 Hz,OCH ₂CH₃), 3.37 (1H, tt, J 10.5, 4.0 Hz, cyclohexaneH-1 or H-4), 3.29(2H, s, COCH₂N), 2.57, 2.56 (4H, 2d AB system, J Hz, 4H of morpholine),2.32-2.26 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.26-2.18 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.94-1.84 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.52-1.42 (2H, m, 2H of cyclohexaneH-2,H-3, H-5, H-6), 1.22 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz,CDCl₃) δ −72.6 (ddd, J 27.0, 7.0, 2.5 Hz), −124.4 ((ddd, J 27.0, 9.5,2.5 Hz); m/z: 657 [M+H]⁺ (found [M+H]⁺, 657.2432, C₃₀H₃₄F₂N₈O₅S requires[M+H]⁺657.2414).

I-29:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylL-valinate

¹H nmr (400 MHz, CDCl₃) δ 11.72 (1H, s, NH), 8.49 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.31 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.16 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.05 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 7.65 (1H, td, J 9.0, 6.5Hz, pyridineH-4 or H-5), 6.88 (1H, dt, J 8.5, 3.0 Hz, pyridineH-4 orH-5), 6.14, 6.10 (2H, 2d AB system, J 10.5 Hz, NCH₂O), 4.26 (1H, tt, J11.5, 4.0 Hz, cyclohexaneH-1 or H-4), 3.45 (2H, q, J 7.0 Hz, OCH ₂CH₃),3.40-3.32 (2H, m, cyclohexaneH-1 or H-4, COCHNH₂), 2.33-2.25 (2H, m, 2Hof cyclohexaneH-2, H-3, H-5, H-6), 2.23-2.17 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 2.05-2.01 (1H, m, CHCH(CH₃)2), 1.94-1.83(2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.51-1.41 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.22 (3H, t, J 7.0 Hz, OCH₂CH ₃), 0.91(3H, d, J 7.0 Hz, 1×CH₃ of CH(CH ₃)₂), 0.82 (3H, d, J 6.5 Hz, 1×CH₃ ofCH(CH ₃)₂); ¹⁹F nmr (380 MHz, CDCl₃) δ −72.7, −124.4; m/z: 629 [M+H]⁺(found [M+H]⁺, 629.2474, C₂₉H₃₄F₂N₈O₄S requires [M+H]⁺ 629.2465).

I-30:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylL-valinate benzenesulfonic acid

¹H nmr (400 MHz, D₆-DMSO) δ 11.47 (1H, s, NH), 8.68 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.53 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.37 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.27 (2H, br s, NH₂),8.24 (1H, s, 1H of pyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.09(1H, td, J 9.5, 6.5 Hz, pyridineH-4 or H-5), 7.69-7.56 (2H, m, 2H of C₆H ₅SO₃H), 7.32-7.24 (4H, m, 3H of C₆ H ₅SO₃H, pyridineH-4 or H-5), 6.34,6.25 (2H, 2d AB system, J 11.0 Hz, NCH₂O), 4.33 (1H, tt, J 11.5, 3.5 Hz,cyclohexaneH-1 or H-4), 4.03 (1H, d, J 4.5 Hz, COCHNH₂), 3.47 (2H, q, J7.0 Hz, OCH ₂CH₃), 3.34 (1H, tt, J 10.5, 4.0 Hz, cyclohexaneH-1 or H-4),2.14-2.06 (5H, m, CHCH(CH₃)₂, 4H of cyclohexaneH-2, H-3, H-5, H-6),1.90-1.80 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.41-1.30 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH₂CH₃), 0.89 (3H, d, J 6.5 Hz, 1×CH₃ of CH(CH₃)₂), 0.86 (3H, d, J 7.0 Hz,1×CH₃ of CH(CH₃)₂); ¹⁹F nmr (380 MHz, D₆-DMSO) δ −72.6, −124.5; n/z: 629[M+H]⁺.

I-31:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylL-valinate methanesulfonic acid salt

¹H nmr (400 MHz, D₆-DMSO) δ 8.68 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.53 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.37 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3 or H-5), 8.34 (2H, br s, NH₂), 8.24 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3 or H-5), 8.09 (1H, dt, J 9.0, 6.5Hz, pyridineH-4 or H-5), 7.26 (1H, ddd, J 9.0, 3.0, 2.5 Hz, pyridineH-4or H-5), 6.34, 6.25 (2H, 2d AB system, J 11.0 Hz, NCH₂O), 4.33 (1H, tt,J 11.5, 3.0 Hz, cyclohexaneH-1 or H-4), 4.04 (1H, t, J 5.0 Hz, COCHNH₂),3.47 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.38-3.30 (1H, m, cyclohexaneH-1 orH-4), 2.31 (3H, s, CH ₃SO₃H), 2.16-2.04 (5H, m, 4H of cyclohexaneH-2,H-3, H-5, H-6, CHCH(CH₃)₂), 1.91-1.80 (2H, m, 2H of cyclohexaneH-2, H-3,H-5, H-6), 1.40-1.30 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.10(3H, t, J 7.0 Hz, OCH₂CH ₃), 0.90 (3H, d, J 7.0 Hz, 1×CH₃ of CH(CH ₃)₂),0.86 (3H, d, J 7.0 Hz, 1×CH₃ of CH(CH ₃)₂); ¹⁹F nmr (380 MHz, D₆-DMSO) δ−73.0, −124.1; m/z: 629 [M+H]⁺.

I-35:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate

¹H nmr (400 MHz, CDCl₃) δ 11.70 (1H, s, NH), 8.48 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.29 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.15 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.04 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 7.63 (1H, td, J 9.0, 6.5Hz, pyridineH-4 or H-5), 6.86 (1H, ddd, J 9.0, 3.0, 2.5 Hz, pyridineH-4or H-5), 6.13, 6.08 (2H, 2d AB system, J 10.5 Hz, NCH₂CO), 4.25 (1H, tt,J 11.5, 4.0 Hz, cyclohexaneH-1 or H-4), 3.54 (2H, q, J 7.0 Hz, OCH₂CH₃), 3.35 (1H, tt, J 11.0, 4.0 Hz, cyclohexaneH-1 or H-4), 3.20 (1H,s, COCH(C(CH₃)₃)NH₂), 2.32-2.24 (2H, m, 2H of cyclohexaneH-2, H-3, H-5,H-6), 2.24-2.16 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.93-1.82(2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.50-1.40 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.20 (3H, t, J 7.0 Hz, OCH₂CH ₃), 0.89(9H, s, C(CH₃)₃); ¹⁹F nmr (380 MHz, CDCl₃) δ −72.6, −124.4; n/z: 643[M+H]⁺ (found [M+H]⁺, 643.2595, C₃₀H₃₇F₂N₈O₄S requires [M+H]⁺643.2621).

I-36:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate benzenesulfonic acid

¹H nmr (400 MHz, D₆-DMSO) δ 11.74 (1H, s, NH), 8.68 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.53 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.37 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.29 (2H, m, 2×NH₂), 8.25(1H, s, 1H of pyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.09 (1H, dt,J 9.5, 6.5 Hz, pyridineH-4 or H-5), 7.59-7.56 (2H, m, 2H of C₆H₅SO₃H),7.32-7.23 (4H, m, 3H of C₆H₅SO₃H, pyridineH-4 or H-5), 6.34, 6.26 (2H,2d AB system, J 11.0 Hz, NCH₂CO), 4.33 (tt, J 11.5, 3.5 Hz,cyclohexaneH-1 or H-4), 3.91 (1H, br s, COCH(C(CH₃)₃)NH₂), 3.47 (2H, q,J 7.0 Hz, OCH ₂CH₃), 3.34 (1H, tt, J 10.5, 3.5 Hz, cyclohexaneH-1 orH-4), 2.12-2.05 (4H, m, 4H of cyclohexaneH-2, H-3, H-5, H-6), 1.92-1.80(2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.41-1.30 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH₂CH ₃), 0.93(9H, s, C(CH₃)₃); ¹³C nmr (100 MHz, D₆-DMSO) δ 168.5, 160.2, 157.5 (d, J234.0 Hz), 157.5, 153.5 (d, J 258.0 Hz), 149.4, 148.9, 139.6 (d, J 7.5Hz), 138.1 (d, J 14.5 Hz), 132.6 (d, J 9.0 Hz), 132.4 (d, J 3.0 Hz),128.7, 128.0, 125.9, 124.4, 121.4, 120.3, 117.9, 76.0, 73.7, 63.0, 60.8,33.7, 30.9 (2C), 26.4, 16.1; ¹⁹F nmr (380 MHz, D₆-DMSO) δ −72.9, −124.1;m/z: 643 [M+H]⁺.

I-37:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl4-(morpholinomethyl)benzoate

¹H nmr (400 MHz, CDCl₃) δ 11.73 (1H, s, NH), 8.50 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.42 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.18 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.06 (1H, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.02 (2H, d, J 8.0 Hz, 2Hof C₆H₄), 7.64 (1H, dt, J 9.0, 6.5 Hz, pyridineH-4 or H-5), 7.42 (1H, d,J 8.0 Hz, 2H of C₆H₄), 6.85 (1H, m, pyridineH-4 or H-5), 6.34 (2H, s,NCH₂CO), 4.27 (1H, tdd, J 11.5, 4.0, 3.5 Hz, cyclohexaneH-1 or H-4),3.70, 3.69 (4H, 2d AB system, J 4.5 Hz, 4H of morpholine), 3.56 (2H, q,J 7.0 Hz, OCH ₂CH₃), 3.54 (2H, s, C₆H₄CH ₂N), 3.37 (1H, tt, J 10.5, 4.0Hz, cyclohexaneH-1 or H-4), 2.42 (4H, br s, 4H of morpholine), 2.32-2.26(2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.26-2.18 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.94-1.84 (2H, m, 2H of cyclohexaneH-2,H-3, H-5, H-6), 1.52-1.42 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6),1.22 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, CDCl₃) δ −72.5,−124.4; m/z: 733 [M+H]⁺.

I-39:(1R,2R)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylicacid

¹H nmr (400 MHz, D₆-DMSO) δ 12.25 (1H, br s, OH), 11.47 (1H, s, NH),8.57 (1H, s, 1H of pyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.52(1H, s, 1H of pyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.34 (1H, 1Hof pyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.19 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.08 (1H, dt, J 9.0, 6.5Hz, pyridineH-4 or H-5), 7.27 (1H, dt, J 8.5, 2.5 Hz, pyridineH-4 orH-5), 6.13, 6.05 (2H, 2d AB system, J 11.0 Hz, NCH₂O), 4.33 (1H, tt, J11.5, 3.5 Hz, cyclohexaneH-1 or H-4), 3.47 (2H, q, J 7.0 Hz, OCH ₂CH₃),3.35 (1H, tt, J 11.0, 3.5 Hz, cyclohexaneH-1 or H-4), 2.78-2.40 (1H, m,cyclohexane dicarboxylic acid H-1 or H-2), 2.12-2.04 (4H, m, 4H ofcyclohexaneH-2, H-3, H-5, H-6), 1.97-1.82 (1H, m, 1H of cyclohexanedicarboxylic acid H-1 or H-2), 1.90-1.81 (4H, m, 2H of cyclohexaneH-2,H-3, H-5, H-6, 2H of cyclohexane dicarboxylic acid H-3, H-4, H-5, H-6),1.65 (2H, br s, cyclohexane dicarboxylic acid H-3, H-4, H-5, H-6),1.39-1.30 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.27-1.17 (4H,m, 4H of cyclohexane dicarboxylic acid H-3, H-4, H-5, H-6), 1.10 (3H, t,J 7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, D₆-DMSO) δ −72.8, −124.2; m/z:684 [M+H]⁺ (found [M+H]⁺, 684.2416, C₃₂H₃₅F₂N₇O₆S requires [M+H]⁺684.2410).

I-40:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate methanesulfonic acid salt

¹H nmr (400 MHz, D₆-DMSO) δ 12.47 (1H, br s, NH), 8.68 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.53 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.37 (1H, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.30 (2H, br s, NH₂), 8.25(1H, s, 1H of pyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.09 (1H, dt,J 9.5, 6.5 Hz, pyridineH-4 or H-5), 7.27 (1H, dt, J 8.5, 2.5 Hz,pyridineH-4 or H-5), 6.34, 6.26 (2H, 2d AB system, J 11.0 Hz, NCH₂O),4.33 (1H, tt, J 11.5, 3.5 Hz, 1H of cyclohexaneH-1 or H-4), 3.90 (1H, d,J 4.5 Hz, COCH(C(CH₃)₃)NH₂), 3.47 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.39-3.31(1H, m, cyclohexaneH-1 or H-4), 2.30 (3H, s, CH ₃SO₃H), 2.12-2.04 (4H,m, 4H of cyclohexaneH-2, H-3, H-5, H-6), 1.90-1.80 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.40-1.30 (2H, m, 2H of cyclohexaneH-2,H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH₂CH ₃), 0.93 (9H, s, C(CH₃)₃);¹³C nmr (100 MHz, D₆-DMSO) δ 168.5, 160.2, 157.6, 157.5 (d, J 236.0 Hz),155.7 (dd, J 260.0, 4.5 Hz), 149.4, 139.5 (d, J 6.5 Hz), 138.2 (t, J14.0 Hz), 132.6 (d, J 8.5 Hz), 132.4, 124.4, 121.4, 120.3, 117.9, 76.0,73.7, 65.4, 63.0, 60.8, 33.7, 30.9 (2C), 26.4, 16.1; ¹⁹F nmr (380 MHz,D₆-DMSO) δ −72.9, −124.0; m/z: 643 [M+H]⁺.

I-42:N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4S)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((2S,3S,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H nmr (400 MHz, D₆-DMSO) δ 11.47 (1H, s, NH), 8.66 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.53 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.32 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.14 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.08 (1H, td, J 9.5, 6.5Hz, pyridineH-4 or H-5), 7.26 (1H, dt, J 8.5, 2.5 Hz, pyridineH-4 orH-5), 5.30 (1H, d, J 6.0 Hz, OH-2), 5.23-5.21 (2H, m, H-1, OH-3), 5.09(1H, d, J 5.5 Hz, OH-4), 4.61 (1H, t, J 5.5 Hz, OH-6), 4.33 (1H, br t, J11.5 Hz, cHexH-1 or H-4), 3.79 (1H, td, J 9.0, 6.0 Hz, H-2), 3.70 (1H,dd, J 11.0, 5.5 Hz, 1×H-6), 3.47 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.45-3.32(3H, m, cHexH-1 or H-4, H-3, 1×H-6), 3.24-3.21 (1H, m, H-4), 2.12-2.04(4H, m, 4H of cHexH-2, H-3, H-5, H-6), 1.91-1.81 (1H, m, 2H of cHexH-2,H-3, H-5, H-6), 1.40-1.31 (2H, m, 2H of cHexH-2, H-3, H-5, H-6), 1.10(3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, D₆-DMSO) δ −72.8, −124.2;m/z: 662 [M+H]⁺ (found [M+H]⁺, 662.2219, C₂₉H₃₃F₂N₇O₇S requires[M+H]⁺662.2203).

I-43:N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4R)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

¹H nmr (400 MHz, D₆-DMSO) δ 11.49 (1H, s, NH), 8.59 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.53 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.33 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.17 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.09 (1H, td, J 9.5, 6.0Hz, pyridineH-4 or H-5), 7.28 (1H, dt, J 8.5, 2.5 Hz, pyridineH-4 orH-5), 5.70 (1H, d, J 4.0 Hz, H-1), 5.15 (1H, br s, 1×OH), 4.93 (2H, brm, 2×OH), 4.54 (1H, br s, 1×OH), 4.39 (1H, t, J 3.5 Hz, H-2), 4.33 (1H,br t, J 11.5 Hz, cHexH-1 or H-4), 3.91 (1H, dd, J 7.0, 3.0 Hz, H-3),3.63 (1H, d, J 10.0 Hz, 1×H-6), 3.58-3.52 (2H, m, H-4, 1×H-6), 3.47 (2H,q, J 7.0 Hz, OCH ₂CH₃), 3.45-3.42 (1H, m, H-5), 3.35 (1H, m, cHexH-1 orH-4), 2.12-2.04 (4H, m, 4H of cHexH-2, H-3, H-5, H-6), 1.92-1.81 (2H, m,2H of cHexH-2, H-3, H-5, H-6), 1.40-1.31 (2H, m, 2H of cHexH-2, H-3,H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, D₆-DMSO)δ −72.7, −124.2; m/z: 662 [M+H]⁺ (found [M+H]⁺, 662.2195, C₂₉H₃₃F₂N₇O₇Srequires [M+H]⁺ 662.2203).

I-49:1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethylhydrogen phosphate tris salt

¹H nmr (400 MHz, D₆-DMSO) δ 11.46 (1H, s, NH), 8.51 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.49 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.28 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.07 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.06 (1H, dt, J 10.0, 6.5Hz, pyridineH-4 or H-5), 7.28 (1H, dt, J 8.5, 2.5 Hz, pyridineH-4 orH-5), 6.12 (1H, dq, J 9.0, 6.0 Hz, NCH(CH₃)OP), 4.32 (1H, br t, J 11.5Hz, cyclohexaneH-1 or H-4), 3.47 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.44 (6H,s, C(CH ₂OH)₃), 3.35 (1H, tt, J 10.5, 3.5 Hz, cyclohexaneH-1 or H-4),2.12-2.05 (4H, m, 4H of cyclohexaneH-2, H-3, H-5, H-6), 1.91-1.81 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.66 (3H, d, J 6.0 Hz, NCH(CH₃)OP), 1.40-1.30 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H,t, J 7.0 Hz, OCH₂CH ₃); ³²P nmr (380 MHz, D₆-DMSO) δ 0.2; ¹⁹F nmr (380MHz, D₆-DMSO) δ −72.6, −124.4; m/z: 624 [M+H]⁺.

I-50:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylglycinate benzenesulfonic acid salt

¹H nmr (400 MHz, D₆-DMSO) δ 11.47 (1H, s, NH), 8.67 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.53 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.37 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.24 (1H, s, 1H ofpyrazoleH-5, thiazoleH-5, pyrazoleH-3, H-5), 8.23 (2H, br s, NH₂), 8.09(1H, dt, J 9.5, 6.5 Hz, pyridineH-4 or H-5), 7.59-7.56 (2H, m, 2H of C₆H ₅SO₃H), 7.32-7.25 (4H, m, 3H of C₆ H ₅SO₃H, pyridineH-4 or H-5), 6.26(2H, s, NCH₂CO), 4.34 (1H, tt, J 11.5, 3.5 Hz, cyclohexaneH-1 or H-4),3.92 (2H, br s, COCH ₂NH₂), 3.47 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.39-3.33(1H, m, cyclohexaneH-1 or H-4), 2.12-2.05 (4H, m, 4H of cyclohexaneH-2,H-3, H-5, H-6), 1.91-1.80 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6),1.41-1.30 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H, t, J7.0 Hz, OCH₂CH ₃); ¹⁹F nmr (380 MHz, D₆-DMSO) δ −73.0, −124.1; m/z: 587[M+H]⁺.

I-56:4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoicacid tris salt

¹H nmr (400 MHz, D₂O) δ 7.52 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3, H-5), 7.49 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3, H-5), 7.16 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3, H-5), 7.13 (1H, s, 1H of pyrazoleH-5, thiazoleH-5,pyrazoleH-3, H-5), 7.13-7.07 (1H, m, pyridineH-4 or H-5), 6.24 (1H, brd, J 8.0 Hz, pyridineH-4 or H-5), 5.69 (2H, s, NCH₂O), 7.39 (1H, br t, J11.5 Hz, cyclohexaneH-1 or H-4), 3.59 (6H, s, 3×CCH ₂OH), 3.55 (2H, q, J7.0 Hz, OCH ₂CH₃), 3.37 (1H, br t, J 10.5 Hz, cyclohexaneH-1 or H-4),2.54 (2H, t, J 6.5 Hz, 2H of COCH₂CH₂CO), 2.39 (2H, t, J 6.5 Hz, 2H ofCOCH₂CH₂CO), 2.12-2.04 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6),2.15-1.98 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.55-1.44 (2H,m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.32-1.21 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹Fnmr (380 MHz, D₂O) δ −73.4, −124.7; m/z: 630 [M+H]⁺.

I-68:N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamidecitric acid cocrystal

¹H nmr (400 MHz, D₆-DMSO) δ 8.53 (1H, s, thiazoleH-5 or pyrazoleH-5),8.29 (3H, s, pyrazoleH-3, H-5, thiazoleH-5 or pyrazoleH-5), 8.08 (1H,td, J 9.0, 6.0 Hz, pyridineH-4 or H-5), 7.29 (1H, ddd, J 9.0, 3.0, 2.5Hz, pyridineH-4 or H-5), 5.14 (0.5H, br s, COH), 4.33 (1H, tt, J 11.5,3.5 Hz, cyclohexaneH-1 or H-4), 3.47 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.35(1H, m, cyclohexaneH-1 or H-4), 2.74, 2.64 (3H, 2d AB system, J 15.5 Hz,3×0.5 CCH ₂CO₂H), 2.08 (4H, m, 4H of cyclohexaneH-2, H-3, H-5, H-6),1.85 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.35 (2H, m, 2H ofcyclohexaneH-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH₂CH ₃); ¹⁹Fnmr (380 MHz, D₆-DMSO) δ −73.0, −124.2; m/z: 500 [M+H]⁺.

I-69:(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyldihydrogen phosphate bis(tris(hydroxymethyl)aminomethane) salt

¹H nmr (400 MHz, D₂O) δ 7.89 (1H, s, thiazoleH-5 or pyrazoleH-5), 7.80(1H, s, thiazoleH-5 or pyrazoleH-5), 7.45 (1H, s, pyrazoleH-3 or H-5),7.44 (1H, s, pyrazoleH-3 or H-5), 7.33 (1H, m, pyridineH-4 or H-5), 6.53(1H, d, J 9.0 Hz, pyridineH-4 or H-5), 5.51 (1H, d, J 6.5 Hz, NCH₂OP),3.93 (1H, tt, J 12.0, 3.0 Hz, cyclohexaneH-1 or H-4), 3.58 (2H, q, J 7.0Hz, OCH ₂CH₃), 3.57 (12H, s, 2×H₂NC(CH ₂OH)₃), 3.45 (1H, m,cyclohexaneH-1 or H-4), 2.14 (2H, br d, J 10.5 Hz, 2H of cyclohexaneH-2,H-3, H-5, H-6), 2.03 (2H, br d, J 12.0 Hz, cyclohexaneH-2, H-3, H-5,H-6), 1.63 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.32 (2H, m, 2Hof cyclohexaneH-2, H-3, H-5, H-6), 1.11 (3H, t, J 7.0 Hz, OCH₂CH ₃); ³¹Pnmr (162 MHz, D₂O) δ 1.05; ¹⁹F nmr (380 MHz, D₂O) δ −72.8 (d, 26.0 Hz),−124.7 (dd, J 27.0, 9.5 Hz); m/z: 610 [M+H]⁺ (found [M+H]⁺, 610.1432,C₂₄H₂₆F₂N₇O₆PS requires [M+H]⁺610.1444).

I-70: Benzyl((S)-1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate

¹H nmr (400 MHz, CDCl₃) δ 8.78 (1H, s, 1H of pyrazoleH-3, H-5), 8.50(1H, s, thiazoleH-5 or pyrazoleH-5), 8.35 (1H, s, 1H of pyrazoleH-3,H-5), 8.14 (1H, s, thiazoleH-5 or pyrazoleH-5), 7.65 (1H, td, J 9.0, 6.0Hz, pyridineH-4 or H-5), 7.35-7.30 (5H, m, C₆H₅), 6.90 (1H, ddd, J 9.0,3.0, 2.5 Hz, pyridineH-4 or H-5), 5.66 (1H, m, NCHCO), 5.50 (1H, d, J9.0 Hz, NH), 5.14, 5.11 (2H, 2d AB system, J 12.5 Hz, OCH ₂C₆H₅), 4.27(1H, tt, J 11.5, 4.0 Hz, cycohexaneH-1 or H-4), 3.56 (2H, q, J 7.0 Hz,OCH ₂CH₃), 3.37 (1H, tt, J 10.5, 4.0 Hz, cyclohexaneH-1 or H-4), 2.29(2H, br d, J 12.0 Hz, 2H of cyclohexaneH-2, H-3, H-5, H-6), 2.22 (2H, m,2H of cyclohexaneH-2, H-3, H-5, H-6), 1.89 (2H, m, 2H of cyclohexaneH-2,H-3, H-5, H-6), 1.82 (2H, m, CHCH ₂CH(CH₃)₂), 1.65 (1H, m,CHCH₂CH(CH₃)₂), 1.47 (2H, m, 2H of cyclohexaneH-2, H-3, H-5, H-6), 1.22(3H, t, J 7.0 Hz, OCH₂CH ₃), 1.07 (2H, br d, J 5.5 Hz, 1×CH(CĤ₃)₂), 0.96(3H, d, J 6.0 Hz, 1×CH(CH ₃)₂); ¹⁹F nmr (380 MHz, CDCl₃) δ −72.5 (d, J27.5 Hz), −124.4 (dd, J 27.0, 9.5 Hz); m/z: 769 [M+Na]⁺, 747 [M+H]⁺(found [M+H]⁺, 747.2885, C₃₇H₄₀F₂N₈O₅S requires [M+H]⁺747.2883).

Example 19

The purpose of the project was to evaluate several salts of compoundI-18. Salts were prepared using 10 bases (two charge ratios for NaOH andKOH). Suitable solvents include, but are not limited to, methanol,DMSO/acetone (1:4 or 4:1), ethyl acetate, THF/water (9:1) or acombination thereof. The salts were isolated by centrifugation and driedunder vacuum. Optionally, the salts also may be heated to dry and/orremove at least a portion of residual solvent.

-   -   1) A disodium salt was obtained by mixing 1 equivalent of I-18        with 2 equivalents of NaOH in a solvent at room temperature.    -   2) A dipotassium salt was obtained by mixing 1 equivalent of        I-18 with 2 equivalents of KOH in a solvent at room temperature.    -   3) A magnesium salt was obtained by mixing equimolar amounts of        I-18 and magnesium hydroxide in a solvent at room temperature.    -   4) A calcium salt was obtained by mixing equimolar amounts of        I-18 and calcium hydroxide in a solvent at room temperature.    -   5) An ammonium salt was obtained by mixing equimolar amounts of        I-18 and ammonium hydroxide in a solvent at room temperature.    -   6) An arginine salt was obtained by mixing equimolar amounts of        I-18 and arginine in a solvent at room temperature.    -   7) A lysine salt was obtained by mixing equimolar amounts of        I-18 and lysine in a solvent at room temperature.    -   8) A choline salt was obtained by mixing equimolar amounts of        I-18 and choline in a solvent at room temperature.    -   9) A tris salt was obtained by mixing equimolar amounts of I-18        and tromethamine in a solvent at room temperature.    -   10) A meglumine salt was obtained by mixing equimolar amounts of        I-18 and meglumine in a solvent at room temperature.    -   11) A monopotassium salt was obtained by mixing equimolar        amounts of 1-18 and KOH in a solvent at room temperature.    -   12) A monosodium salt was obtained by mixing equimolar amounts        of I-18 and NaOH in a solvent at room temperature.

All salt hits were characterized by XRPD, TGA and DSC. Thestoichiometric ratio was determined by 1H NMR or HPLC/IC.Characterization results of salt hits and freeform forms were listed inTable 5.

TABLE 5 Characterization results of initial salts Weight loss DSCendotherm Molar ratio Speculated Salt Hits (%, temp.) (peak, ° C.)(base/free acid) form K Salt 3.1 (to 150° C.) 170.3, 248.1 0.7:1Anhydrate/ Hydrate K Salt 5.3 (to 140° C.)  94.6*, 174.0* 1.1:1 Hydrate    6.7 (140° C.~240° C.) K Salt 4.0 (to 130° C.) 101.7*, 168.5* 1.0:1Hydrate     4.7 (130° C.~230° C.) K Salt 5.9 (to 125° C.) 100.6, 149.01.4:1 Anhydrate Arginine Salt 2.1 (to 190° C.) 130.7, 216.1 1.2:1Anhydrate Choline Salt 5.1 (to 160° C.) 67.7, 158.7, 195.0 0.8:1Anhydrate Choline Salt 3.3 (to 160° C.) 67.2, 159.4, 195.7 NA Anhydrate/Hydrate Tris Salt 1.2 (to 150° C.)  61.3, 174.3 1.1:1 Channel hydrateTris Salt 2.4 (to 140° C.) 63.0, 135.2, 175.6 0.9:1 Channel hydrate NaSalt) 5.5 (to 240° C.) 97.6, 176.4, 195.0 1.5:1 Anhydrate/     6.0 (110°C.~240° C.) Hydrate Na Salt 13.5 (to 250° C.)  109.9, 183.1, 226.0 1.6:1Anhydrate/ Hydrate Na Salt 6.1 (to 150° C.) 66.6, 110.7, 200.7 1.6:1Anhydrate/ Hydrate Ammonium Salt 3.0 (to 115° C.) 97.9, 160.2, 0.6:1^(#) Anhydrate/     2.6 (115° C.~200° C.) 192.9, 238.8 HydrateArginine Salt) 4.0 (to 160° C.) 80.8, 119.4, 1.0:1 Anhydrate/ 145.1,177.1 Hydrate Lysine Salt 5.0 (to 140° C.) 69.3, 175.4, 227.3 0.7:1Anhydrate/ Hydrate Mg Salt 11.7 (to 230° C.)  69.4, 116.4, 183.2 1.0:1^(#) Anhydrate/ Hydrate Ca Salt 6.9 (to 180° C.) 114.0*, 190.5* 0.8:1^(#) Anhydrate/ Hydrate *Onset temperature. ^(#)Solid could not bedissolved completely before HPLC and IC test, so the stoichiometricratio was for reference only.

Based on the above, a potassium salt, arginine salt, choline salt andtris salt were selected for further evaluation.

TABLE 6 Characterization of evaluation salts TGA weight loss DSCendotherm Molar ratio Salt form (%, temp.) (° C., peak) (base/API) Ksalt 6.6 (to 220° C.) 199.8  1:1 Arginine salt 3.3 (to 190° C.) 131.6,217.1  1:1 Choline salt 2.3 (to 160° C.)  64.3, 186.7 0.9:1 Tris salt5.8 (to 150° C.) 156.5, 176.2 1.1:1

Hygroscopicity Evaluation

To investigate the solid form stability as a function of humidity, DVSisotherm plot of the K salt, Arginine salt, Choline salt and Tris saltwere collected at 25° C. between 0 and 95% RH. The DVS plot of the Ksalt is shown in FIG. 20 . The water uptake at 70% RH was 0.42%, andincreased dramatically to 16.5% at 95% RH. The DVS plot of Arginine saltis shown in FIG. 21 . A water uptake of 1.43% was observed at 80% RH,indicating Arginine salt was slight hygroscopic. The DVS plot of Cholinesalt is shown in FIG. 22 . The water uptake at 70% RH was 3.66%, andincreased dramatically to 32.4% at 95% RH. The DVS plot of Tris salt isshown in FIG. 23 . The water uptake at 70% RH was 6.06%, and increaseddramatically to 39.5% at 95% RH.

Physical and Chemical Stability

The physical and chemical stability of the K salt, Arginine salt,Choline salt and Tris salt were evaluated under conditions of 25° C./60%RH and 40° C./75% RH for 1 week. Each sample was added into 3 mL glassvials, sealed by parafilm with several holes, and kept under testedcondition. After one week, samples was taken for XRPD and HPLC puritytest. All the characterization data are summarized in Table 7.

TABLE 7 Summary of physiochemical stability evaluation 25° C./60% 40°C./75% RH/1 week RH/1 week Initial Purity/ Purity/ purity Initial FormInitial Form Salt (area %) purity (%) change purity (%) change K salt97.27 99.0 No 99.1 Yes Arginine salt 95.91 99.4 No 99.6 No Choline salt98.70 100.0 No 99.1 No Tris salt 96.06 100.6 No 98.9 No

The XRPD patterns showed that no form change was observed after storageunder the two conditions for the Arginine salt, Choline salt and Trissalt. For the K salt, no form change was observed under 25° C./60% RHwhile a form change was observed under 40° C./75% RH. For both the Ksalt and Arginine salt, a slight purity decrease was observed under bothconditions after 1 week. For Choline salt and Tris salt, no HPLC puritydecrease was observed under 25° C./60% RH while a purity decrease wasobserved under 40° C./75% RH. Impurities summary for all salt hits areshown in Tables 8-11. The peak at RRT=1.17 corresponds to 1-1, theparent compound of 1-18 that is formed by hydrolysis. Decrease in purityof 1-18 salt is typically correlated with a corresponding increase inI-1 parent impurity level.

TABLE 8 Impurity summary of the potassium salt Area (%) # Peak RRTInitial 25° C./60% RH 40° C./75% RH 1 1.00 97.27 96.26 96.40 2 1.14<0.04 <0.04 0.05 3 1.17 1.33 2.14 1.80 4 1.40 0.23 0.25 0.39 5 1.44 0.210.30 0.24 6 1.70 0.18 0.27 0.24 7 1.72 0.77 0.78 0.83 8 1.81 <0.04 <0.040.04

TABLE 9 Impurity summary of the arginine salt Area (%) # Peak RRTInitial 25° C./60% RH 40° C./75% RH 1 0.77 <0.03 0.03 0.04 2 1.00 95.9195.31 95.50 3 1.13 <0.03 0.06 0.06 4 1.17 2.39 2.68 2.48 5 1.35 <0.030.06 0.11 6 1.45 0.44 0.50 0.47 7 1.71 0.73 0.74 0.73 8 1.73 <0.53 0.610.60

TABLE 10 Impurity summary of the choline salt Area (%) # Peak RRTInitial 25° C./60% RH 40° C./75% RH 1 0.77 0.03 0.04 0.04 2 1.00 98.7098.66 97.81 3 1.13 0.06 0.06 0.06 4 1.17 0.75 0.58 1.31 5 1.35 <0.030.10 0.14 6 1.45 0.06 0.07 0.11 7 1.71 0.06 0.05 0.08 8 1.73 0.33 0.460.46

TABLE 11 Impurity summary of the tris salt Area (%) # Peak RRT Initial25° C./60% RH 40° C./75% RH 1 0.77 <0.03 <0.03 0.03 2 1.00 96.06 96.6195.03 3 1.13 0.07 0.06 0.06 4 1.17 1.87 1.63 2.69 5 1.45 0.37 0.35 0.476 1.71 0.86 0.80 0.88 7 1.73 0.76 0.55 0.84

In view of the many possible embodiments to which the principles of thedisclosed invention may be applied, it should be recognized that theillustrated embodiments are only preferred examples of the invention andshould not be taken as limiting the scope of the invention. Rather, thescope of the invention is defined by the following claims. We thereforeclaim as our invention all that comes within the scope and spirit ofthese claims.

We claim:
 1. A compound that is sodium1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethylhydrogen phosphate.
 2. A composition comprising the compound of claim 1,and a pharmaceutically acceptable excipient.
 3. A method for treating adisease or condition for which an IRAK inhibitor is indicated,comprising administering to a subject having the disease or condition aneffective amount of a compound according to claim 1 or a compositionthereof, wherein the disease or condition comprises an auto-immunedisease, inflammatory disorder, cardiovascular disease,neurodegenerative disorder, allergic disorder, multi-organ failure,kidney disease, platelet aggregation, cancer, transplantation, spermmotility, erythrocyte deficiency, graft rejection, lung injury,respiratory disease, ischemic condition, bacterial infection, viralinfection, immune regulatory disorder or a combination thereof.
 4. Themethod of claim 3, wherein the disease or condition comprises anautoimmune disease, inflammatory disorder, cardiovascular disease,cancer, ischemic condition, immune regulatory disorder or a combinationthereof.
 5. The method of claim 3, wherein the disease or conditioncomprises an autoimmune disease or inflammatory disorder.
 6. The methodof claim 3, wherein the disease or condition comprises a proliferativedisorder.
 7. The method of claim 3, wherein the disease or conditioncomprises transplant or organ rejection, a graft-versus-host disease,rheumatoid arthritis, systemic lupus erythematosus, Hashimoto'sthyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis,type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis,glomerulonephritis, rheumatic fever, post-infectious glomerulonephritis,inflammatory skin disease, hyperproliferative skin disease, psoriasis,atopic dermatitis, contact dermatitis, eczematous dermatitis,seborrhoeic dermatitis, lichen planus, pemphigus, bullous pemphigoid,epidermolysis bullosa, urticaria, angioedemas, vasculitis, erythema,cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata,keratoconjunctivitis, vernal conjunctivitis, uveitis associated withBehcet's disease, keratitis, herpetic keratitis, conical cornea,dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus,Mooren's ulcer, scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Haradasyndrome, sarcoidosis, pollen allergies, reversible obstructive airwaydisease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsicasthma, dust asthma, chronic or inveterate asthma, late asthma andairway hyper-responsiveness, bronchitis, gastric ulcers, vascular damagecaused by ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns, celiac diseases, proctitis,eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerativecolitis, migraine, rhinitis, eczema, interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy,multiple myositis, Guillain-Barre syndrome, Meniere's disease,polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjögren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenesis, metastasis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis, sclerosing cholangitis, partial liver resection,acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock,or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis,alcoholic liver disease, including alcoholic cirrhosis, non-alcoholicsteatohepatitis (NASH), hepatic failure, fulminant hepatic failure,late-onset hepatic failure, “acute-on-chronic” liver failure,augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMVinfection, AIDS, cancer, senile dementia, Parkinson's disease, trauma,chronic bacterial infection, or a combination thereof.
 8. The method ofclaim 3, wherein the disease or condition comprises a lymphoid neoplasmselected from myeloproliferative neoplasms (MPN) excluding polycythemiavera, myeloid/lymphoid neoplasms with PDGFRA rearrangement,myeloid/lymphoid neoplasms with PDGFRB rearrangement, myeloid/lymphoidneoplasms with FGFR1 rearrangement, myeloid/lymphoid neoplasms withPCM1-JAK2, Myelodysplastic/myeloproliferative neoplasms (MDS/MPN),myeloid sarcoma, myeloid proliferations related to Down syndrome,blastic plasmacytoid dendritic cell neoplasm, B-lymphoblasticleukemia/lymphoma, T-lymphoblastic leukemia/lymphoma, or a combinationthereof.
 9. The method of claim 3, wherein the disease or conditioncomprises rheumatoid arthritis, psoriatic arthritis, osteoarthritis,systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis,osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, inparticular pustular psoriasis, type I diabetes, type II diabetes,inflammatory bowel disease (Crohn's disease and ulcerative colitis),hyperimmunoglobulinemia d and periodic fever syndrome,cryopyrin-associated periodic syndromes, Schnitzler's syndrome, systemicjuvenile idiopathic arthritis, adult-onset Still's disease, gout, goutflares, pseudogout, sapho syndrome, Castleman's disease, sepsis, stroke,atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptorantagonist), Alzheimer's disease, Parkinson's disease or a combinationthereof.
 10. The method of claim 6, wherein the proliferative disordercomprises a disorder selected from benign tumors, malignant tumors,solid tumor, carcinoma of the brain, kidney, liver, adrenal gland,bladder, breast, stomach, gastric tumors, ovaries, colon, rectum,prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract,esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas,neuroblastomas, multiple myeloma, gastrointestinal cancer, coloncarcinoma or colorectal adenoma, a tumor of the neck and head, anepidermal hyperproliferation, psoriasis, prostate hyperplasia, aneoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, Hodgkins and non-Hodgkins, amammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, IL-1 driven disorders, a MyD88driven disorder (such as ABC diffuse large B-cell lymphoma (DLBCL),Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneousT-cell lymphoma, smoldering or indolent multiple myeloma, hematologicalmalignancies, leukemia, acute myeloid leukemia (AML), DLBCL, ABC DLBCL,chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma,primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocyticleukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma,myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera,Kaposi's sarcoma, Waldenström's macroglobulinemia (WM), splenic marginalzone lymphoma, multiple myeloma, plasmacytoma, intravascular largeB-cell lymphoma, or a combination thereof.
 11. The method of claim 6,wherein the proliferative disorder comprises psoriasis.
 12. The methodof claim 12, wherein the proliferative disorder comprises a drugresistant malignancy.
 13. The method of claim 12, wherein the drugresistant malignancy comprises a malignancy selected from malignanciesresistant to JAK inhibitors, ibrutinib resistant malignancies, ibrutinibresistant hematological malignancies, ibrutinib resistant CLL, ibrutinibresistant, Waldenström's macroglobulinemia or a combination thereof. 14.The method of claim 3, wherein the disease or condition comprises ahematological malignancy.
 15. The method of claim 14, wherein thehematological malignancy comprises a malignancy selected from leukemia,acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocyticleukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma,Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cellprolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplasticsyndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma,Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma,multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma.16. The method of claim 3, wherein the disease or condition comprises ahyperproliferative skin disorder.
 17. The method of claim 3, wherein thedisease or condition comprises an inflammatory skin disease, psoriasis,primary biliary cirrhosis, sclerosing cholangitis, systemic juvenileidiopathic arthritis, atopic dermatitis, contact dermatitis, eczematousdermatitis, or seborrhoeic dermatitis.
 18. The method of claim 3,further comprising administering a second therapeutic agent.
 19. Themethod of claim 18, wherein the second therapeutic agent is ananalgesic, an antibiotic, an anticoagulant, an antibody, ananti-inflammatory agent, an immunosuppressant, a guanylate cyclase-Cagonist, an intestinal secretagogue, an antiviral, anticancer,antifungal, or a combination thereof.